Research
Original Investigation
Association of Metabolic Syndrome and Hidradenitis Suppurativa Iben Marie Miller, MD; Christina Ellervik, MD, PhD; Gabrielle Randskov Vinding, MD; Kian Zarchi, MD; Kristina Sophie Ibler, MD; Kim Mark Knudsen, PhD; Gregor B. E. Jemec, DMSc, MD Editorial page 1263 IMPORTANCE An association between the metabolic syndrome (MetS) and chronic
inflammatory diseases, such as psoriasis or rheumatoid arthritis, has been suggested. Hidradenitis suppurativa (HS), a more localized chronic inflammation of the skin, has been speculated to have a similar association. Hidradenitis suppurativa is a substantial burden for the individual and a socioeconomic burden globally. Information about the burden of possible comorbidities is scarce.
Supplemental content at jamadermatology.com
OBJECTIVE To investigate the possibility of an association between HS and MetS. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional population- and hospital-based study of HS and MetS. We identified 32 patients with physician-verified HS from the outpatient clinic at the Department of Dermatology, Roskilde Hospital, and 326 patients with HS and 14 851 individuals without HS from the general population. Individuals with HS were younger, predominantly female, and more often smokers compared with the non-HS group. EXPOSURE Hidradenitis suppurativa. MAIN OUTCOMES AND MEASURES Metabolic syndrome and its components of diabetes mellitus, hypertension, dyslipidemia, and obesity. RESULTS When compared with the non-HS group, the odds ratios (ORs) for the hospital HS and population HS groups were 3.89 (95% CI, 1.90-7.98) and 2.08 (95% CI, 1.61-2.69), respectively, for MetS; 5.74 (95% CI, 1.91-17.24) and 2.44 (95% CI, 1.55-3.83), respectively, for diabetes mellitus; 6.38 (95% CI, 2.99-13.62) and 2.56 (95% CI, 2.00-3.28), respectively, for general obesity; and 3.62 (95% CI, 1.73-7.60) and 2.24 (95% CI, 1.78-2.82), respectively, for abdominal obesity. With regard to dyslipidemia, significant results were found for decreased levels of high-density lipoprotein cholesterol, with ORs of 2.97 (95% CI, 1.45-6.08) and 1.94 (95% CI, 1.52-2.48) for the hospital HS and general population HS groups, respectively, when compared with the non-HS group. With regard to increased triglyceride levels, only the result for the population HS group compared with the non-HS group was significant, with an OR of 1.49 (95% CI, 1.18-1.87). The OR for hypertension, which was only significant for the hospital HS group compared with the non-HS group, was 2.14 (95% CI, 1.01-4.53). Obesity and inflammation acted as possible confounders. The ORs were higher for the hospital HS group compared with the population HS group. The association between HS and MetS was not influenced by the degree of HS severity. CONCLUSIONS AND RELEVANCE As with more systemic inflammatory diseases, HS appears to be associated with MetS, indicating substantial comorbidities. Because this study is cross-sectional, causality remains to be explored.
JAMA Dermatol. 2014;150(12):1273-1280. doi:10.1001/jamadermatol.2014.1165 Published online September 17, 2014.
Author Affiliations: Department of Dermatology, Roskilde Hospital, Roskilde, Denmark (Miller, Vinding, Zarchi, Ibler, Jemec); Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (Miller, Jemec); Department of Clinical Biochemistry, Næstved Hospital, Næstved, Denmark (Ellervik); LEO Pharma A/S, Ballerup, Denmark (Knudsen). Corresponding Author: Iben Marie Miller, MD, Department of Dermatology, Roskilde Hospital, Køgevej 7-13, 4000 Roskilde, Denmark ([email protected]).
1273
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Purdue University User on 06/09/2015
Research Original Investigation
Hidradenitis Suppurativa
H
idradenitis suppurativa (HS) is a chronic, localized inflammatory skin disease producing inflamed nodules in apocrine gland–bearing skin.1,2 The treatment of HS is often inadequate, and the disease inflicts a significant burden on patients, in whom pain and suppuration from lesions often lead to inactivity, depression, and significantly impaired quality of life.3,4 Changes in patients’ socioprofessional activity indicate the presence of important diseaserelated impairment.5,6 Hidradenitis suppurativa may be more common than hitherto suggested. The disease is often misdiagnosed or underdiagnosed, and prevalence estimates therefore range from 0.05% to 4%.7-10 An increasing incidence during the last 20 years has been suggested.11 The comorbidities of HS are poorly described, and the available data are solely hospital based.12,13 The pandemic cluster of cardiovascular risk factors called the metabolic syndrome (MetS) co-occurs more commonly with chronic inflammatory diseases, such as rheumatoid arthritis and psoriasis.14-18 In contrast to psoriasis, HS may be considered a more localized inflammation of the skin. An association between HS and MetS has been hypothesized to exist and cause significant comorbidity, negatively influencing the overall burden of disease. We therefore investigated a possible association using population- and hospital-based data in a cross-sectional study to explore the association and assess its possible clinical relevance.
Methods Ethical Statement This study was accepted by the ethics committee of the Zealand region (project numbers SJ-191, SJ-113, and SJ-114) in Denmark. Written informed consent was obtained from all study participants.
ity of 90% and a specificity of 97%. The overall participation rate in GESUS was 49.3%. Further details about GESUS can be found in Bergholdt et al.19 The hospital HS group was recruited from the outpatient clinic at the Department of Dermatology at Roskilde Hospital (serving the region of Zealand, which includes Næstved). Inclusion criteria consisted of the diagnostic code for HS from the International Classification of Diseases, 10th Revision (L73.2) and systemic or laser treatment for HS, which indicated moderate or severe disease. The diagnosis of HS was confirmed by results of a physical examination by a physician from the Department of Dermatology (I.M.M., G.R.V., K.Z., or K.S.I.). Eligible patients were invited to undergo the same examination as the population sample. The participation rate was 33 of 98 eligible patients (33.7%). The distribution of age and sex did not differ between participants and nonparticipants (data not shown). Non-HS participants were defined as participants from GESUS without HS. This population constituted the non-HS group for this study. Outcomes Both HS groups and the population-based non-HS group completed the same questionnaire and physical examinations and contributed blood samples. The definitions of the MetS outcome were based on the methods of GESUS involving the GESUS questionnaire (self-reporting), physical examination, and laboratory evaluation of nonfasting venous blood samples.19 The MetS involves the following 4 key components: diabetes mellitus, hypertension, dyslipidemia, and obesity. The methods of this study used to define the outcome are listed in Box 1 and Box 2.20-24 We used a modified version of the criteria of the National Cholesterol Education Program Adult Treatment Panel III,20 which also accounts for the harmonized definition of MetS.
Study Design We performed a cross-sectional study of the association of HS (referred to as the exposure) and MetS (referred to as the outcome). We investigated 2 different groups of individuals with HS. The first group was identified in a general population sample (population HS group); the second was identified in a hospital-based sample (hospital HS group). Exposure The population HS group was identified in the Danish General Suburban Population Study (GESUS). GESUS was initiated in January 2010 with ongoing enrollment and is a crosssectional study of the adult Danish suburban general population in the Næstved municipality (70 km south of Copenhagen).19 All citizens 30 years and older and a random selection of those aged 20 to 30 years were invited to participate. The population HS group was defined based on whether participants reported boils within the previous 6 months and a minimum of 2 boils (in the following 5 possible locations: axillae, groin, genitals, mammae, or other [eg, perianal, neck, or abdomen]) on a questionnaire. The validation of this HS diagnosis is discussed in a separate report5 showing a sensitiv1274
Exploring Possible Confounders We considered the following possible confounders: 1. General obesity defined by body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) measured at the physical examination; 2. Inflammatory load defined by high-sensitivity C-reactiveprotein level measured in venous blood samples; 3. Self-reported level of physical activity at work and in leisure time; 4. Self-reported intake of atherogenic (ie, saturated) fat, fish, fruit/vegetables, eggs, and alcohol.
Exploring the Severity of HS The definition of severity of HS for the population HS group was based on self-reported information on numbers and locations of boils and subsequent scarring and was inspired by the Hurley score, which is considered almost static.25 Mild HS was defined as a minimum of 2 boils and no subsequent scarring; moderate HS, a minimum of 2 boils and subsequent scarring; and severe HS, a minimum of 2 boils in a minimum of 2 locations and subsequent scarring. The
JAMA Dermatology December 2014 Volume 150, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Purdue University User on 06/09/2015
jamadermatology.com
Hidradenitis Suppurativa
Original Investigation Research
Box 1. Definition of Metabolic Syndrome
Box 2. Metabolic Syndrome Component Outcomes
Metabolic syndrome according to a modified version of the US NCEP ATP III includes ⱖ3 of the following criteria:
Diabetes Mellitus
Abdominal Obesity
1. Self-reported diagnosis or based on analysis of the blood sample: HbA1c level of ⱖ48 mmol/mol (IFCC) (ⱖ6.5% DCCT) or nonfasting plasma glucose level of ⱖ220 mg/dL 2. Self-reported use of insulin or noninsulin antidiabetic
WC of >102 cm for men and >88 cm for women based on the physical examination findings Dyslipidemia
1. Decreased plasma HDL levels of 88 cm for women, based on physical examination findings
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); DCCT, Diabetes Control and Complications Trial; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein cholesterol; IFCC, International Federation of Clinical Chemistry; NCEP ATP III, National Cholesterol Education Program Adult Treatment Panel III; TC, total cholesterol; TG, triglycerides; WC, waist circumference. SI conversion factors: To convert cholesterol to millimoles per liter, multiply by 0.0259; glucose to millimoles per liter, multiply by 0.0555; TG to millimoles per liter, multiply by 0.0113.
The ORs and RMs for the population HS group are expressed as ORpop and RMpop. Similarly, ORs and RMs for the hospital HS group are expressed as ORhos and RMhos. We examined the influence of possible confounders on the association between HS and MetS by including these in the regression model and assessing the effect on the OR. We explored the relationship between the severity of HS and MetS
jamadermatology.com
JAMA Dermatology December 2014 Volume 150, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Purdue University User on 06/09/2015
1275
Research Original Investigation
Hidradenitis Suppurativa
Table. Background Factors, Characteristics, and Distribution of Outcome in Study Groupsa HS Groups Characteristic Age, mean (range), y Sex, female vs male, No. (%)
Hospital (n = 32) 42 (22-64) 25 (78) vs 7 (22)
Population (n = 326)
Non-HS Group (n = 14 851)
47 (22-78)
56 (20-96)
218 (67) vs 108 (33)
8090 (54.5) vs 6761 (45.5)
Smoking status, No. (%) Present
17 (53.1)
133 (40.8)
2683 (18.1)
Past
13 (40.6)
114 (35.0)
5633 (37.9)
1 (3.1)
70 (21.5)
5684 (38.3)
Ethnicity, white, No. (%)
Never
31 (96.9)
315 (96.6)
14 624 (98.5)
CRP level, median (range), mg/L
5.1 (0.2-119.0)
2.1 (0.1-38.0)
1.4 (0.1-136.0)
HS severity distribution, % Mild
4 (12.5)
165 (50.6)
Moderate
5 (15.6)
90 (27.6)
NA
23 (71.9)
71 (21.8)
NA
Severe
NA
Sartorius score, median (range)
29 (5-176)
NA
NA
No. of boils, median (range)
12 (1-171)
3 (2-106)
NA
MetS, No. (%)b
17 (53.1)
Diabetes mellitus, No. (%)c
105 (32.2)
3192 (21.5)
4 (12.5)
23 (7.1)
728 (4.9)
18 (56.3)
157 (48.2)
9007 (60.6)
Decreased HDL level
15 (46.9)
108 (33.1)
2687 (18.1)
Increased TG level
16 (50.0)
159 (48.8)
6428 (43.3)
General (BMI)
16 (50.0)
107 (32.8)
2799 (18.8)
Abdominal (WC)
20 (62.5)
168 (51.5)
5524 (37.2)
Hypertension, No. (%)d Blood sample, No. (%)
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); CRP, C-reactive protein; HDL, high-density lipoprotein cholesterol; HS, hidradenitis suppurativa; MetS, metabolic syndrome; NA, not applicable; TG, triglycerides; WC, waist circumference. SI conversion factor: To convert CRP to nanomoles per liter, multiply by 9.524. a
Missing data for groups are reported in eTable 5 in the Supplement.
b
Indicates a modified Adult Treatment Panel III definition.20
c
Indicates self-reported or based on results of laboratory analysis of venous blood sample.
d
Indicates self-reported or measured during the physical examination.
Obesity, No. (%)
using the same regression method as above analyzing only the HS groups. All statistical analyses were performed using commercially available software (SAS, version 9.3; SAS, Inc). Owing to differences in background factors between exposed and unexposed groups and knowledge from previous studies that age, sex, and smoking status act as confounders in cardiovascular risk, the effect measures were adjusted accordingly. In eTables 1 and 2 in the Supplement, crude ORs and RMs are displayed.
Results The data used from GESUS were collected from January 1, 2010, through August 2, 2012. A total of 32 individuals with HS from the hospital, 326 with HS from the general population, and 14 851 non-HS individuals from the general population were identified. The background factors and characteristics of the HS and non-HS groups showed that individuals with HS were predominately younger, female, and smokers (Table). We investigated the association of HS with the conditions involved in the MetS—diabetes mellitus, hypertension, dyslipidemia, and obesity—and with MetS defined by the criteria of the National Cholesterol Education Program Adult Treatment Panel III.20 The methods used to define the outcome are described in Box 1 and Box 2. The ORs and RMs adjusted for age, sex, and smoking status are illustrated in Figure 1 and Figure 2. 1276
Association of MetS and MetS Components With HS When adjusting for age, sex, and smoking status, the association between HS and MetS was significant for the hospital and population HS groups (ORhos, 3.89 [95% CI, 1.90-7.98]; ORpop, 2.08 [95% CI, 1.61-2.69]). Findings for the associations of MetS components with HS are discussed individually. We found a uniform pattern of the hospital HS group having higher ORs than the population HS group. Diabetes Mellitus When adjusting for age, sex, and smoking status, a significant association between HS and diabetes mellitus was found for the hospital and population HS groups compared with the non-HS group (ORhos, 5.74 [95% CI, 1.91-17.24]; ORpop, 2.44 [95% CI, 1.55-3.83]). When we explored the type of antidiabetic used (insulin or noninsulin), only the association of noninsulin drugs was significant (ORhos, 7.93 [95% CI, 1.75-36.03]; ORpop, 3.50 [95% CI, 2.05-5.98]). When quantifying the association, only the RMhos was significant, with levels 8% (95% CI, 2%-15%) and 10% (95% CI, 5%-15%) higher for the HS groups compared with the non-HS group with regard to glucose and hemoglobin A1c levels, respectively. Hypertension When adjusting for age, sex, and smoking status, a significant association between HS and hypertension was found only for the hospital HS group (ORhos, 2.14 [95% CI, 1.01-4.53]). When quantifying this association, only the RMhos for diastolic blood
JAMA Dermatology December 2014 Volume 150, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Purdue University User on 06/09/2015
jamadermatology.com
Hidradenitis Suppurativa
Original Investigation Research
pressure was significant, with a level 5% (95% CI, 1%-10%) higher in the HS hospital group when compared with the non-HS group. Dyslipidemia When adjusting for age, sex, and smoking status, an association between HS and high triglyceride (TG) levels was found, but the association was statistically significant for the population HS group only (ORpop, 1.49 [95% CI, 1.18-1.87]). A significant association between HS and low levels of highdensity lipoprotein cholesterol (HDL) was found (ORhos, 2.97 [95% CI, 1.45-6.08]; ORpop, 1.94 [95% CI, 1.52-2.48]). When quantifying the association, the RMpop for TG level was 21% (95% CI, 0%-46%) and the RMhos was 11% (95% CI, 4%-17%), significantly higher than in the non-HS group. The RMhos for HDL level was 14% (95% CI, 5%-22%) and the RMpop was 10% (95% CI, 7%-13%), significantly lower than in the non-HS group. Obesity When adjusting for age, sex, and smoking status, we found a significant association between general obesity by BMI and abdominal obesity by waist circumference (WC) for the population and hospital HS groups. With regard to general obesity, the ORhos was 6.38 (95% CI, 2.99-13.62) and the ORpop was 2.56 (95% CI, 2.00-3.28). With regards to abdominal obesity, the ORhos was 3.62 (95% CI, 1.73-7.60) and the ORpop was 2.24 (95% CI, 1.78-2.82). When we quantified the association, the RMhos for BMI was 21% (95% CI, 14%-29%) and the RMpop was 9% (95% CI, 7%11%), significantly higher for the HS groups than the non-HS group. The RMhos for WC was 14% (95% CI, 9%-19%) and the RMpop was 7% (95% CI, 6%-9%), significantly higher for the HS groups than the non-HS group.
Role of Obesity, Inflammatory Load, Physical Activity, Diet, and HS Severity When exploring the possible confounders, we found that adjusting for obesity or inflammatory load reduced the strengths of the associations; however, the associations remained. Thus, obesity and inflammation were identified confounders, whereas level of physical activity and diet were not (eTable 3 in the Supplement). The association between HS and MetS or between HS and the MetS components was not influenced by the degree of HS severity with the exception of general obesity (eTable 4 in the Supplement).
Discussion This broad population- and hospital-based study suggests an association between HS and MetS and the individual MetS components of diabetes mellitus, low levels of HDL, and general and abdominal obesity. Positive associations were also found with regard to hypertension and dyslipidemia. Hypertension, however, was only statistically significant in the hospital HS group. When we used binary data (with acknowledged cutoff values) for increased levels of
Figure 1. Hidradenitis Suppurativa (HS) and the Metabolic Syndrome Hospital HS group vs non-HS group Population HS group vs non-HS group
OR (95% CI)
Outcome Metabolic syndrome
3.89 (1.90-7.98) 2.08 (1.61-2.69)
Diabetes mellitus
5.74 (1.91-17.24) 2.44 (1.55-3.83)
Hypertension
2.14 (1.01-4.53) 1.08 (0.85-1.38)
Increased TG level
1.67 (0.81-3.44) 1.49 (1.18-1.87)
Decreased HDL level
2.97 (1.45-6.08) 1.94 (1.52-2.48)
General obesity
6.38 (2.99-13.62) 2.58 (2.00-3.23)
Abdominal obesity
3.62 (1.73-7.60) 2.24 (1.78-2.82)
Negative Association
Positive Association
0.50 1.00 2.00
5.00 10.00 20.00
Odds Ratio
Odds ratios (ORs) for the binary outcomes of the metabolic syndrome and its component outcomes (diabetes mellitus, hypertension, increased triglyceride [TG] levels and decreased high-density lipoprotein cholesterol [HDL] levels, and general and abdominal obesity). The ORs are adjusted for age, sex, and smoking status. Whiskers indicate 95% confidence intervals.
TG, only the association for the population HS group was statistically significant. However, statistically significant differences in the TG levels between the hospital HS group and the non-HS group were found when we examined the continuous data. The hospital HS group had uniformly higher ORs than the population HS group. This result could indicate that differences in HS severity or the recent suggestion of different HS subtypes may play a part.26 This difference might also be an expression of a dilution of the population-based HS sample due to misclassification bias. The stronger ORs for the hospital HS group may also indicate detection bias; that is, HS patients within the hospital system are more likely to have been diagnosed with the outcome, which influences the self-reported diagnoses. However, detection bias was minimized by the inclusion of self-reported diagnosis and results of the physical examination and laboratory analysis of blood samples. When we examined the MetS components individually, the ORs for diabetes mellitus indicated a positive association, mainly due to type 2 diabetes mellitus. Quantification analysis demonstrated that nonfasting glucose level was 1% to 8% higher, and hemoglobin A1c level was 1% to 10% higher in the HS groups compared with the non-HS group. Previous studies have suggested that an approximately 1% reduction in hemoglobin A1c level may decrease the risk for myocardial infarction by 14% to 16%, indicating that the abnormalities seen in the HS patients have clinical significance.27 Further indirect support for this association is provided by the observation that metformin hydrochloride treatment may ameliorate HS.28
jamadermatology.com
JAMA Dermatology December 2014 Volume 150, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Purdue University User on 06/09/2015
1277
Research Original Investigation
Hidradenitis Suppurativa
Figure 2. Hidradenitis Suppurativa (HS) and the Components of the Metabolic Syndrome Hospital HS vs non-HS groups Population HS vs non-HS groups
Component
RM (95% CI)
Nonfasting blood glucose level
1.08 (1.02-1.15) 1.01 (0.99-1.03)
HbA1c level (IFCC)
1.10 (1.05-1.15) 1.01 (1.00-1.03)
Diastolic blood pressure
1.05 (1.01-1.10) 1.01 (1.00-1.02)
Systolic blood pressure
1.02 (0.97-1.07) 0.99 (0.98-1.01)
TG level
1.21 (1.00-1.46) 1.11 (1.04-1.17)
HDL level
0.88 (0.78-0.95) 0.90 (0.87-0.93)
LDL level
0.94 (0.84-1.06) 0.99 (0.96-1.03)
TC level
0.96 (0.90-1.06) 0.98 (0.96-1.00)
General obesity, BMI
1.21 (1.14-1.29) 1.09 (1.07-1.11)
Abdominal obesity, WC
1.14 (1.09-1.19) 1.07 (1.06-1.09)
Negative Association
0.80
Positive Association
1.00
1.20
1.40
1.60
Ratio of Means
Furthermore, the ORs for general and abdominal obesity were significant. When quantified, BMI was 9% to 21% greater, and WC was 7% to 14% larger in the HS groups than the non-HS group. Trimming of the WC by 4.4 cm from 102 cm (ie, a 4.3% reduction) may reduce the risk for diabetes mellitus by 58%, similarly indicating clinical relevance and a substantial potential for prevention in this generally neglected disease.29 The association of an atherogenic lipid profile (ie, increased TG levels and decreased HDL levels) was significant with regard to the decrease in HDL levels in both HS groups, but only significant with regard to the increase in TG levels in the population HS group. When quantified, the HS groups had an 11% to 21% higher TG level and a 10% to 14% lower HDL level than the non-HS group. A follow-up study of the effects of statins in 17 802 healthy individuals showed a significant reduction of cardiovascular events when TG levels were reduced by 17% and HDL levels were increased by 4%.30 Having hypertension was only significant with regard to the hospital HS group. When quantifying the hospital HS group, only the diastolic blood pressure was significantly increased by 5%. A recent meta-analysis of preventive treatment of hypertension suggested that lowering diastolic blood pressure from 90 to 85 mm Hg (ie, a 6% reduction) would reduce the risk for cardiovascular heart disease and stroke by approximately 20% and 30%, respectively.31 Our findings are in concordance with and expand the findings of 2 previous hospital-based studies.12,13 In aggregate, these data therefore suggest that the comorbidities of HS are clinically significant and that an increased clinical awareness of the 1278
Ratio of means (RMs) for continuous outcomes of the components of the metabolic syndrome (nonfasting blood glucose level, hemoglobin A1c [HbA1c] level, diastolic and systolic blood pressure, triglyceride [TG] blood level, high-density lipoprotein cholesterol [HDL] level, low-density lipoprotein cholesterol [LDL] level, total cholesterol [TC] level, general obesity, and abdominal obesity). The RMs are adjusted for age, sex, and smoking status. Whiskers indicate 95% confidence intervals. BMI indicates body mass index (calculated as weight in kilograms divided by height in meters squared); IFCC, International Federation of Clinical Chemistry; WC, waist circumference.
HS diagnosis and its comorbidities might be warranted in this potentially substantial group of patients. Obesity and inflammatory load were identified as possible confounders, partly but not exclusively explaining the associations and indicating a complex and overlapping relationship. Surprisingly, we found that physical activity level, diet and alcohol consumption, and the severity of HS did not influence the associations. The latter is in contrast to our supposition that the hospital HS group had higher ORs because of more severe disease, implying detection bias as previously discussed or an insufficiently sensitive measure of disease severity. Therefore, one can speculate that HS subtypes may influence the association with MetS more strongly than HS severity. The association of MetS has also been shown in the chronic generalized inflammatory disease rheumatoid arthritis and the skin disease psoriasis, for which the ORs for MetS are approximately 2.00 compared with almost 6.00 in HS.8 Furthermore, the associations in psoriasis have been suggested to be significant only with regard to a hospital-based HS cohort,8 implying that the burden of these comorbidities is greater for HS than for psoriasis. Therefore, the common etiological factors between inflammatory skin disease and MetS are more readily identified in HS than in psoriasis. The major strengths of our study are the large populationbased HS group and the inclusion of individuals with HS from hospital- and population-based groups. The broad recruitment reduced selection bias with a broader range of disease severities and thereby aided the generalization of the results. To explore misclassification bias of individuals with HS, we vali-
JAMA Dermatology December 2014 Volume 150, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Purdue University User on 06/09/2015
jamadermatology.com
Hidradenitis Suppurativa
Original Investigation Research
dated the HS definition with a sensitivity of 90% and a specificity of 97%.9 Because the self-reported questions used to identify HS patients refer to symptoms (ie, boils) rather than the actual diagnosis (ie, do you have HS?), we strove to optimize the inclusion of individuals with undiagnosed and misdiagnosed HS in the population, which is particularly pertinent for underdiagnosed diseases. The diagnosis of HS among hospitalized participants was physician verified. The combined methods of selfreporting, laboratory analysis of blood samples, and physical examination aimed to reduce false-negative findings with regard to the outcome (MetS). Finally, essential possible confounders were recognized and explored systematically. Potential limitations merit consideration. First, one must recognize that, because this study is cross-sectional, we cannot prove causality between HS and MetS. Furthermore, the population is suburban, most of the participants were white, and the group aged 20 to 30 years was underrepresented, which may limit the generalizability of our findings. In addition, an age bias was found between the HS and non-HS groups. However, we accommodated this age bias by age adjustments. The low participation rate of the hospital HS group increased varia-
ARTICLE INFORMATION Accepted for Publication: May 1, 2014. Published Online: September 17, 2014. doi:10.1001/jamadermatol.2014.1165. Author Contributions: Drs Miller and Jemec had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Miller, Ellervik, Vinding, Ibler, Jemec. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Miller, Ibler, Jemec. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Miller, Knudsen. Obtained funding: Miller, Ellervik, Jemec. Administrative, technical, or material support: Miller, Vinding, Ibler, Jemec. Study supervision: Ellervik, Ibler, Jemec. Conflict of Interest Disclosures: Dr Jemec has received consulting fees from Abbott Laboratories, AstraZeneca, MSD, Novartis, Pfizer, and DumexAlpharma; lecture fees from Abbott Laboratories, Galderma, Pfizer, and Roche; grant support from Abbott Laboratories, Pfizer, Photocure, and LEO Pharma; equipment on loan from Michelson Diagnostics; and reimbursement for travel expenses from Abbott Laboratories, Galderma, and Photocure. No other disclosures were reported.
tion and reduced power. The low participation rate may be an expression of the limited resources of HS patients due to the physical and mental burden of the disease. Nonfasting blood samples were used. However, differences in fasting and nonfasting lipid levels have been shown to be minimal.32 Furthermore, we did not include information on HS medical treatment, which might confound the results. Last, as with any questionnaire survey, the risk for recall bias was present.
Conclusions The data suggest an association between HS and the MetS in the hospital and population HS groups. This allegedly increased disease burden due to comorbidities indicates that HS patients require general medical attention beyond the skin. Future longitudinal studies with similar methods are needed to explore the temporal relationship of these associations. These studies should be large, include individuals with HS from the general population and hospital, and explore the differences between these groups and additional possible confounders.
of the grant supporting this study, was involved in analysis and interpretation of data and manuscript revision. The funding organizations had no other role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: Claus Bay, MSc Stat, Jørgen Iversen, BSc, and Torsten Skov, MD, PhD, Department of Biostatistics, LEO Pharma, provided statistical, technical, and epidemiological support. Birgitte Schnack Nielsen, clinical nutritionist, Department of Pediatrics, Roskilde Hospital, Denmark, provided information on diet. The contributors did not receive compensation. REFERENCES 1. Kurzen H, Kurokawa I, Jemec GB, et al. What causes hidradenitis suppurativa? Exp Dermatol. 2008;17(5):455-472. 2. Jemec GBE. Clinical practice: hidradenitis suppurativa. N Engl J Med. 2012;366(2):158-164. 3. Matusiak L, Bieniek A, Szepietowski JC. Psychophysical aspects of hidradenitis suppurativa. Acta Derm Venereol. 2010;90(3):264-268. 4. Esmann S, Jemec GBE. Psychosocial impact of hidradenitis suppurativa: a qualitative study. Acta Derm Venereol. 2011;91(3):328-332. 5. Jemec GBE, Heidenheim M, Nielsen NH. Hidradenitis suppurativa: characteristics and consequences. Clin Exp Dermatol. 1996;21(6):419-423.
suppurativa: results from two case-control studies. J Am Acad Dermatol. 2008;59(4):596-601. 9. Vinding GR, Miller IM, Zarchi K, et al. The prevalence of inverse recurrent suppuration: a population-based study of possible hidradenitis suppurativa. Br J Dermatol. 2014;170(4):884-889. 10. Jemec GBE, Heidenheim M, Nielsen NH. The prevalence of hidradenitis suppurativa and its potential precursor lesions. J Am Acad Dermatol. 1996;35(2, pt 1):191-194. 11. Vazquez BG, Alikhan A, Weaver AL, Wetter DA, Davis MD. Incidence of hidradenitis suppurativa and associated factors: a population-based study of Olmsted County, Minnesota. J Invest Dermatol. 2013; 133(1):97-103. 12. Sabat R, Chanwangpong A, Schneider-Burrus S, et al. Increased prevalence of metabolic syndrome in patients with acne inversa. PLoS One. 2012;7 (2):e31810. doi:10.1371/journal.pone.0031810. 13. Gold DA, Reeder VJ, Mahan MG, et al. The prevalence of metabolic syndrome in patients with hidradenitis suppurativa. J Am Acad Dermatol. 2014;70(4):699-703. 14. Miller IM, Ellervik C, Yazdanyar S, Jemec GB. Meta-analysis of psoriasis, cardiovascular disease, and associated risk factors. J Am Acad Dermatol. 2013;69(6):1014-1024. 15. Miller IM, Skaaby T, Ellervik C, Jemec GB. Quantifying cardiovascular disease risk factors in patients with psoriasis: a meta-analysis. Br J Dermatol. 2013;169(6):1180-1187.
Funding/Support: This study was supported by a grant under the Industrial PhD Programme and grants from the Danish Agency for Science, Technology, and Innovation and LEO Pharma (Dr Miller) and by the Jacob Madsen & Olga Madsens Foundation. The GESUS study was supported by the Johan and Lise Boserup Foundation, Trygfonden, Det Kommunale Momsfond, Johannes Fogs Foundation, Region Zealand Foundation, Næstved Hospital, Næstved Hospital Foundation, and the National Board of Health.
6. von der Werth JM, Williams HC. The natural history of hidradenitis suppurativa. J Eur Acad Dermatol Venereol. 2000;14(5):389-392.
16. Miller IM, Jemec GBE. Maturation of an idea: a historical perspective on the association of psoriasis with the metabolic syndrome and cardiovascular disease [letter]. Arch Dermatol. 2012;148(1):112.
7. Cosmatos I, Matcho A, Weinstein R, Montgomery MO, Stang P. Analysis of patient claims data to determine the prevalence of hidradenitis suppurativa in the United States. J Am Acad Dermatol. 2013;68(3):412-419.
17. Ferraz-Amaro I, González-Juanatey C, López-Mejias R, et al. Metabolic syndrome in rheumatoid arthritis. Mediators Inflamm. 2013; 2013:710928. doi:10.1155/2013/710928.
Role of the Funder/Sponsor: Dr Knudsen, who is an employee of LEO Pharma, which provided part
8. Revuz JE, Canoui-Poitrine F, Wolkenstein P, et al. Prevalence and factors associated with hidradenitis
jamadermatology.com
18. Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C; National Heart, Lung, and Blood
JAMA Dermatology December 2014 Volume 150, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Purdue University User on 06/09/2015
1279
Research Original Investigation
Hidradenitis Suppurativa
Institute; American Heart Association. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Arterioscler Thromb Vasc Biol. 2004;24(2):e13-e18. 19. Bergholdt HK, Bathum L, Kvetny J, et al. Study design, participation and characteristics of the Danish General Suburban Population Study. Dan Med J. 2013;60(9):A4693. 20. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285(19):2486-2497. 21. Alberti KG, Eckel RH, Grundy SM, et al; International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International
Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120(16):1640-1645.
27. Macisaac RJ, Jerums G. Intensive glucose control and cardiovascular outcomes in type 2 diabetes. Heart Lung Circ. 2011;20(10):647-654.
22. International Expert Committee. International Expert Committee report on the role of the A1c assay in the diagnosis of diabetes. Diabetes Care. 2009;32(7):1327-1334.
28. Verdolini R, Clayton N, Smith A, Alwash N, Mannello B. Metformin for the treatment of hidradenitis suppurativa: a little help along the way. J Eur Acad Dermatol Venereol. 2013;27(9):1101-1108.
23. Institute for Rational Pharmacotherapy in Denmark. Guidelines on diabetes. Månedsbladet rationel farmakoterapi. 2006;8. www.irf.dk. Accessed May 21, 2014.
29. Tuomilehto J, Lindström J, Eriksson JG, et al; Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344(18):1343-1350.
24. Chobanian AV, Bakris GL, Black HR, et al; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289(19):2560-2572. 25. Sartorius K, Lapins J, Emtestam L, Jemec GB. Suggestions for uniform outcome variables when reporting treatment effects in hidradenitis suppurativa. Br J Dermatol. 2003;149(1):211-213. 26. Canoui-Poitrine F, Le Thuaut A, Revuz JE, et al. Identification of three hidradenitis suppurativa phenotypes: latent class analysis of a cross-sectional study. J Invest Dermatol. 2013;133(6):1506-1511.
30. Ridker PM, Danielson E, Fonseca FA, et al; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21): 2195-2207. 31. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009;338:b1665. doi:10.1136/bmj.b1665. 32. Langsted A, Freiberg JJ, Nordestgaard BG. Fasting and nonfasting lipid levels: influence of normal food intake on lipids, lipoproteins, apolipoproteins, and cardiovascular risk prediction. Circulation. 2008;118(20):2047-2056.
NOTABLE NOTES
Apple of the Dermatologist’s Eye Deshan F. Sebaratnam, MBBS(Hons)
Dermatology is an intrinsically visual specialty, with pattern recognition a vital skill for clinical practice. It therefore follows that many of the classic descriptions of cutaneous pathologic abnormalities draw on parallels from the natural world, particularly the realm of botany. Trees, leaves, fruits, and flowers have all lent themselves to morphological descriptions over the centuries. The distribution of the papulosquamous plaques of pityriasis rosea has been compared to a fir tree and the hair shaft changes of trichorrhexis nodosa to bamboo. The figurate polycyclic plaques of erythema gyratum repens have been described as resembling wood grain and the jagged forked lesions of livedo racemosa tree branches.1 The induration associated with scleroderma is classically described as woody, and the neurofibromas of neurofibromatosis are said to have a rubbery consistency. Lichenification derives its name from lichen (a composite organism of fungi and algae living symbiotically), and the tumors of mycosis fungoides were initially thought to be fungal growths (though strictly speaking, the kingdom of Fungi is separate from that of plants). The ovate shape of the hypopigmented macules of tuberous sclerosis has been compared to ash leaves, and the color of Zoon balanitis has been described as resembling that of fallen autumn leaves. Fruits have inspired a range of dermatological descriptions, including peau d’orange, tapioca vesicles in pompholyx, and cayenne pepper spots in pigmented purpuric dermatoses. The berries are particularly well represented through strawberry birthmarks, mulberry xanthomas, and cherry angiomas.
1280
Flowers have also given rise to dermatological descriptions, such as the heliotrope rash of dermatomyositis, which originates from the lilac color of flowers of the genus Heliotropium.2 Perhaps the plant that has inspired the greatest number of wordsmiths within dermatology and beyond is the rose. Varicella zoster virus gives rise to “dew drops on a rose petal,” human herpes virus is associated with roseola infantum, and Salmonella typhi produces rose spots. The rosette is a well-recognized sign reported in a range of descriptions: clinically, as in linear IgA disease; dermoscopically, as in squamous cell carcinoma3; and pathologically, as in cylindromas. The visual nature of dermatology lends itself to comparisons between cutaneous pathological abnormalities and those seen in the botanical world, with several classical descriptions firmly “implanted” into the dermatological canon. Author Affiliation: Skin and Cancer Foundation Australia, Department of Dermatology, Westmead, NSW, Australia. Corresponding Author: Deshan F. Sebaratnam, Skin and Cancer Foundation Australia, 7 Ashley Lane, Westmead, NSW 2154, Australia ([email protected]). 1. Parsi K, Partsch H, Rabe E, Ramelet AA. Reticulate eruptions, part 2: historical perspectives, morphology, terminology and classification. Australas J Dermatol. 2011;52(4):237-244. 2. Russo T, Piccolo V, Ruocco E, Baroni A. The heliotrope sign of dermatomyositis: the correct meaning of the term heliotrope. Arch Dermatol. 2012;148(10):1178. 3. Rubegni P, Tataranno DR, Nami N, Fimiani M. Rosettes: optical effects and not dermoscopic patterns related to skin neoplasms. Australas J Dermatol. 2013;54(4):271-272.
JAMA Dermatology December 2014 Volume 150, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Purdue University User on 06/09/2015
jamadermatology.com
Original Investigation
Association of Metabolic Syndrome and Hidradenitis Suppurativa Iben Marie Miller, MD; Christina Ellervik, MD, PhD; Gabrielle Randskov Vinding, MD; Kian Zarchi, MD; Kristina Sophie Ibler, MD; Kim Mark Knudsen, PhD; Gregor B. E. Jemec, DMSc, MD Editorial page 1263 IMPORTANCE An association between the metabolic syndrome (MetS) and chronic
inflammatory diseases, such as psoriasis or rheumatoid arthritis, has been suggested. Hidradenitis suppurativa (HS), a more localized chronic inflammation of the skin, has been speculated to have a similar association. Hidradenitis suppurativa is a substantial burden for the individual and a socioeconomic burden globally. Information about the burden of possible comorbidities is scarce.
Supplemental content at jamadermatology.com
OBJECTIVE To investigate the possibility of an association between HS and MetS. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional population- and hospital-based study of HS and MetS. We identified 32 patients with physician-verified HS from the outpatient clinic at the Department of Dermatology, Roskilde Hospital, and 326 patients with HS and 14 851 individuals without HS from the general population. Individuals with HS were younger, predominantly female, and more often smokers compared with the non-HS group. EXPOSURE Hidradenitis suppurativa. MAIN OUTCOMES AND MEASURES Metabolic syndrome and its components of diabetes mellitus, hypertension, dyslipidemia, and obesity. RESULTS When compared with the non-HS group, the odds ratios (ORs) for the hospital HS and population HS groups were 3.89 (95% CI, 1.90-7.98) and 2.08 (95% CI, 1.61-2.69), respectively, for MetS; 5.74 (95% CI, 1.91-17.24) and 2.44 (95% CI, 1.55-3.83), respectively, for diabetes mellitus; 6.38 (95% CI, 2.99-13.62) and 2.56 (95% CI, 2.00-3.28), respectively, for general obesity; and 3.62 (95% CI, 1.73-7.60) and 2.24 (95% CI, 1.78-2.82), respectively, for abdominal obesity. With regard to dyslipidemia, significant results were found for decreased levels of high-density lipoprotein cholesterol, with ORs of 2.97 (95% CI, 1.45-6.08) and 1.94 (95% CI, 1.52-2.48) for the hospital HS and general population HS groups, respectively, when compared with the non-HS group. With regard to increased triglyceride levels, only the result for the population HS group compared with the non-HS group was significant, with an OR of 1.49 (95% CI, 1.18-1.87). The OR for hypertension, which was only significant for the hospital HS group compared with the non-HS group, was 2.14 (95% CI, 1.01-4.53). Obesity and inflammation acted as possible confounders. The ORs were higher for the hospital HS group compared with the population HS group. The association between HS and MetS was not influenced by the degree of HS severity. CONCLUSIONS AND RELEVANCE As with more systemic inflammatory diseases, HS appears to be associated with MetS, indicating substantial comorbidities. Because this study is cross-sectional, causality remains to be explored.
JAMA Dermatol. 2014;150(12):1273-1280. doi:10.1001/jamadermatol.2014.1165 Published online September 17, 2014.
Author Affiliations: Department of Dermatology, Roskilde Hospital, Roskilde, Denmark (Miller, Vinding, Zarchi, Ibler, Jemec); Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (Miller, Jemec); Department of Clinical Biochemistry, Næstved Hospital, Næstved, Denmark (Ellervik); LEO Pharma A/S, Ballerup, Denmark (Knudsen). Corresponding Author: Iben Marie Miller, MD, Department of Dermatology, Roskilde Hospital, Køgevej 7-13, 4000 Roskilde, Denmark ([email protected]).
1273
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Purdue University User on 06/09/2015
Research Original Investigation
Hidradenitis Suppurativa
H
idradenitis suppurativa (HS) is a chronic, localized inflammatory skin disease producing inflamed nodules in apocrine gland–bearing skin.1,2 The treatment of HS is often inadequate, and the disease inflicts a significant burden on patients, in whom pain and suppuration from lesions often lead to inactivity, depression, and significantly impaired quality of life.3,4 Changes in patients’ socioprofessional activity indicate the presence of important diseaserelated impairment.5,6 Hidradenitis suppurativa may be more common than hitherto suggested. The disease is often misdiagnosed or underdiagnosed, and prevalence estimates therefore range from 0.05% to 4%.7-10 An increasing incidence during the last 20 years has been suggested.11 The comorbidities of HS are poorly described, and the available data are solely hospital based.12,13 The pandemic cluster of cardiovascular risk factors called the metabolic syndrome (MetS) co-occurs more commonly with chronic inflammatory diseases, such as rheumatoid arthritis and psoriasis.14-18 In contrast to psoriasis, HS may be considered a more localized inflammation of the skin. An association between HS and MetS has been hypothesized to exist and cause significant comorbidity, negatively influencing the overall burden of disease. We therefore investigated a possible association using population- and hospital-based data in a cross-sectional study to explore the association and assess its possible clinical relevance.
Methods Ethical Statement This study was accepted by the ethics committee of the Zealand region (project numbers SJ-191, SJ-113, and SJ-114) in Denmark. Written informed consent was obtained from all study participants.
ity of 90% and a specificity of 97%. The overall participation rate in GESUS was 49.3%. Further details about GESUS can be found in Bergholdt et al.19 The hospital HS group was recruited from the outpatient clinic at the Department of Dermatology at Roskilde Hospital (serving the region of Zealand, which includes Næstved). Inclusion criteria consisted of the diagnostic code for HS from the International Classification of Diseases, 10th Revision (L73.2) and systemic or laser treatment for HS, which indicated moderate or severe disease. The diagnosis of HS was confirmed by results of a physical examination by a physician from the Department of Dermatology (I.M.M., G.R.V., K.Z., or K.S.I.). Eligible patients were invited to undergo the same examination as the population sample. The participation rate was 33 of 98 eligible patients (33.7%). The distribution of age and sex did not differ between participants and nonparticipants (data not shown). Non-HS participants were defined as participants from GESUS without HS. This population constituted the non-HS group for this study. Outcomes Both HS groups and the population-based non-HS group completed the same questionnaire and physical examinations and contributed blood samples. The definitions of the MetS outcome were based on the methods of GESUS involving the GESUS questionnaire (self-reporting), physical examination, and laboratory evaluation of nonfasting venous blood samples.19 The MetS involves the following 4 key components: diabetes mellitus, hypertension, dyslipidemia, and obesity. The methods of this study used to define the outcome are listed in Box 1 and Box 2.20-24 We used a modified version of the criteria of the National Cholesterol Education Program Adult Treatment Panel III,20 which also accounts for the harmonized definition of MetS.
Study Design We performed a cross-sectional study of the association of HS (referred to as the exposure) and MetS (referred to as the outcome). We investigated 2 different groups of individuals with HS. The first group was identified in a general population sample (population HS group); the second was identified in a hospital-based sample (hospital HS group). Exposure The population HS group was identified in the Danish General Suburban Population Study (GESUS). GESUS was initiated in January 2010 with ongoing enrollment and is a crosssectional study of the adult Danish suburban general population in the Næstved municipality (70 km south of Copenhagen).19 All citizens 30 years and older and a random selection of those aged 20 to 30 years were invited to participate. The population HS group was defined based on whether participants reported boils within the previous 6 months and a minimum of 2 boils (in the following 5 possible locations: axillae, groin, genitals, mammae, or other [eg, perianal, neck, or abdomen]) on a questionnaire. The validation of this HS diagnosis is discussed in a separate report5 showing a sensitiv1274
Exploring Possible Confounders We considered the following possible confounders: 1. General obesity defined by body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) measured at the physical examination; 2. Inflammatory load defined by high-sensitivity C-reactiveprotein level measured in venous blood samples; 3. Self-reported level of physical activity at work and in leisure time; 4. Self-reported intake of atherogenic (ie, saturated) fat, fish, fruit/vegetables, eggs, and alcohol.
Exploring the Severity of HS The definition of severity of HS for the population HS group was based on self-reported information on numbers and locations of boils and subsequent scarring and was inspired by the Hurley score, which is considered almost static.25 Mild HS was defined as a minimum of 2 boils and no subsequent scarring; moderate HS, a minimum of 2 boils and subsequent scarring; and severe HS, a minimum of 2 boils in a minimum of 2 locations and subsequent scarring. The
JAMA Dermatology December 2014 Volume 150, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Purdue University User on 06/09/2015
jamadermatology.com
Hidradenitis Suppurativa
Original Investigation Research
Box 1. Definition of Metabolic Syndrome
Box 2. Metabolic Syndrome Component Outcomes
Metabolic syndrome according to a modified version of the US NCEP ATP III includes ⱖ3 of the following criteria:
Diabetes Mellitus
Abdominal Obesity
1. Self-reported diagnosis or based on analysis of the blood sample: HbA1c level of ⱖ48 mmol/mol (IFCC) (ⱖ6.5% DCCT) or nonfasting plasma glucose level of ⱖ220 mg/dL 2. Self-reported use of insulin or noninsulin antidiabetic
WC of >102 cm for men and >88 cm for women based on the physical examination findings Dyslipidemia
1. Decreased plasma HDL levels of 88 cm for women, based on physical examination findings
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); DCCT, Diabetes Control and Complications Trial; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein cholesterol; IFCC, International Federation of Clinical Chemistry; NCEP ATP III, National Cholesterol Education Program Adult Treatment Panel III; TC, total cholesterol; TG, triglycerides; WC, waist circumference. SI conversion factors: To convert cholesterol to millimoles per liter, multiply by 0.0259; glucose to millimoles per liter, multiply by 0.0555; TG to millimoles per liter, multiply by 0.0113.
The ORs and RMs for the population HS group are expressed as ORpop and RMpop. Similarly, ORs and RMs for the hospital HS group are expressed as ORhos and RMhos. We examined the influence of possible confounders on the association between HS and MetS by including these in the regression model and assessing the effect on the OR. We explored the relationship between the severity of HS and MetS
jamadermatology.com
JAMA Dermatology December 2014 Volume 150, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Purdue University User on 06/09/2015
1275
Research Original Investigation
Hidradenitis Suppurativa
Table. Background Factors, Characteristics, and Distribution of Outcome in Study Groupsa HS Groups Characteristic Age, mean (range), y Sex, female vs male, No. (%)
Hospital (n = 32) 42 (22-64) 25 (78) vs 7 (22)
Population (n = 326)
Non-HS Group (n = 14 851)
47 (22-78)
56 (20-96)
218 (67) vs 108 (33)
8090 (54.5) vs 6761 (45.5)
Smoking status, No. (%) Present
17 (53.1)
133 (40.8)
2683 (18.1)
Past
13 (40.6)
114 (35.0)
5633 (37.9)
1 (3.1)
70 (21.5)
5684 (38.3)
Ethnicity, white, No. (%)
Never
31 (96.9)
315 (96.6)
14 624 (98.5)
CRP level, median (range), mg/L
5.1 (0.2-119.0)
2.1 (0.1-38.0)
1.4 (0.1-136.0)
HS severity distribution, % Mild
4 (12.5)
165 (50.6)
Moderate
5 (15.6)
90 (27.6)
NA
23 (71.9)
71 (21.8)
NA
Severe
NA
Sartorius score, median (range)
29 (5-176)
NA
NA
No. of boils, median (range)
12 (1-171)
3 (2-106)
NA
MetS, No. (%)b
17 (53.1)
Diabetes mellitus, No. (%)c
105 (32.2)
3192 (21.5)
4 (12.5)
23 (7.1)
728 (4.9)
18 (56.3)
157 (48.2)
9007 (60.6)
Decreased HDL level
15 (46.9)
108 (33.1)
2687 (18.1)
Increased TG level
16 (50.0)
159 (48.8)
6428 (43.3)
General (BMI)
16 (50.0)
107 (32.8)
2799 (18.8)
Abdominal (WC)
20 (62.5)
168 (51.5)
5524 (37.2)
Hypertension, No. (%)d Blood sample, No. (%)
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); CRP, C-reactive protein; HDL, high-density lipoprotein cholesterol; HS, hidradenitis suppurativa; MetS, metabolic syndrome; NA, not applicable; TG, triglycerides; WC, waist circumference. SI conversion factor: To convert CRP to nanomoles per liter, multiply by 9.524. a
Missing data for groups are reported in eTable 5 in the Supplement.
b
Indicates a modified Adult Treatment Panel III definition.20
c
Indicates self-reported or based on results of laboratory analysis of venous blood sample.
d
Indicates self-reported or measured during the physical examination.
Obesity, No. (%)
using the same regression method as above analyzing only the HS groups. All statistical analyses were performed using commercially available software (SAS, version 9.3; SAS, Inc). Owing to differences in background factors between exposed and unexposed groups and knowledge from previous studies that age, sex, and smoking status act as confounders in cardiovascular risk, the effect measures were adjusted accordingly. In eTables 1 and 2 in the Supplement, crude ORs and RMs are displayed.
Results The data used from GESUS were collected from January 1, 2010, through August 2, 2012. A total of 32 individuals with HS from the hospital, 326 with HS from the general population, and 14 851 non-HS individuals from the general population were identified. The background factors and characteristics of the HS and non-HS groups showed that individuals with HS were predominately younger, female, and smokers (Table). We investigated the association of HS with the conditions involved in the MetS—diabetes mellitus, hypertension, dyslipidemia, and obesity—and with MetS defined by the criteria of the National Cholesterol Education Program Adult Treatment Panel III.20 The methods used to define the outcome are described in Box 1 and Box 2. The ORs and RMs adjusted for age, sex, and smoking status are illustrated in Figure 1 and Figure 2. 1276
Association of MetS and MetS Components With HS When adjusting for age, sex, and smoking status, the association between HS and MetS was significant for the hospital and population HS groups (ORhos, 3.89 [95% CI, 1.90-7.98]; ORpop, 2.08 [95% CI, 1.61-2.69]). Findings for the associations of MetS components with HS are discussed individually. We found a uniform pattern of the hospital HS group having higher ORs than the population HS group. Diabetes Mellitus When adjusting for age, sex, and smoking status, a significant association between HS and diabetes mellitus was found for the hospital and population HS groups compared with the non-HS group (ORhos, 5.74 [95% CI, 1.91-17.24]; ORpop, 2.44 [95% CI, 1.55-3.83]). When we explored the type of antidiabetic used (insulin or noninsulin), only the association of noninsulin drugs was significant (ORhos, 7.93 [95% CI, 1.75-36.03]; ORpop, 3.50 [95% CI, 2.05-5.98]). When quantifying the association, only the RMhos was significant, with levels 8% (95% CI, 2%-15%) and 10% (95% CI, 5%-15%) higher for the HS groups compared with the non-HS group with regard to glucose and hemoglobin A1c levels, respectively. Hypertension When adjusting for age, sex, and smoking status, a significant association between HS and hypertension was found only for the hospital HS group (ORhos, 2.14 [95% CI, 1.01-4.53]). When quantifying this association, only the RMhos for diastolic blood
JAMA Dermatology December 2014 Volume 150, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Purdue University User on 06/09/2015
jamadermatology.com
Hidradenitis Suppurativa
Original Investigation Research
pressure was significant, with a level 5% (95% CI, 1%-10%) higher in the HS hospital group when compared with the non-HS group. Dyslipidemia When adjusting for age, sex, and smoking status, an association between HS and high triglyceride (TG) levels was found, but the association was statistically significant for the population HS group only (ORpop, 1.49 [95% CI, 1.18-1.87]). A significant association between HS and low levels of highdensity lipoprotein cholesterol (HDL) was found (ORhos, 2.97 [95% CI, 1.45-6.08]; ORpop, 1.94 [95% CI, 1.52-2.48]). When quantifying the association, the RMpop for TG level was 21% (95% CI, 0%-46%) and the RMhos was 11% (95% CI, 4%-17%), significantly higher than in the non-HS group. The RMhos for HDL level was 14% (95% CI, 5%-22%) and the RMpop was 10% (95% CI, 7%-13%), significantly lower than in the non-HS group. Obesity When adjusting for age, sex, and smoking status, we found a significant association between general obesity by BMI and abdominal obesity by waist circumference (WC) for the population and hospital HS groups. With regard to general obesity, the ORhos was 6.38 (95% CI, 2.99-13.62) and the ORpop was 2.56 (95% CI, 2.00-3.28). With regards to abdominal obesity, the ORhos was 3.62 (95% CI, 1.73-7.60) and the ORpop was 2.24 (95% CI, 1.78-2.82). When we quantified the association, the RMhos for BMI was 21% (95% CI, 14%-29%) and the RMpop was 9% (95% CI, 7%11%), significantly higher for the HS groups than the non-HS group. The RMhos for WC was 14% (95% CI, 9%-19%) and the RMpop was 7% (95% CI, 6%-9%), significantly higher for the HS groups than the non-HS group.
Role of Obesity, Inflammatory Load, Physical Activity, Diet, and HS Severity When exploring the possible confounders, we found that adjusting for obesity or inflammatory load reduced the strengths of the associations; however, the associations remained. Thus, obesity and inflammation were identified confounders, whereas level of physical activity and diet were not (eTable 3 in the Supplement). The association between HS and MetS or between HS and the MetS components was not influenced by the degree of HS severity with the exception of general obesity (eTable 4 in the Supplement).
Discussion This broad population- and hospital-based study suggests an association between HS and MetS and the individual MetS components of diabetes mellitus, low levels of HDL, and general and abdominal obesity. Positive associations were also found with regard to hypertension and dyslipidemia. Hypertension, however, was only statistically significant in the hospital HS group. When we used binary data (with acknowledged cutoff values) for increased levels of
Figure 1. Hidradenitis Suppurativa (HS) and the Metabolic Syndrome Hospital HS group vs non-HS group Population HS group vs non-HS group
OR (95% CI)
Outcome Metabolic syndrome
3.89 (1.90-7.98) 2.08 (1.61-2.69)
Diabetes mellitus
5.74 (1.91-17.24) 2.44 (1.55-3.83)
Hypertension
2.14 (1.01-4.53) 1.08 (0.85-1.38)
Increased TG level
1.67 (0.81-3.44) 1.49 (1.18-1.87)
Decreased HDL level
2.97 (1.45-6.08) 1.94 (1.52-2.48)
General obesity
6.38 (2.99-13.62) 2.58 (2.00-3.23)
Abdominal obesity
3.62 (1.73-7.60) 2.24 (1.78-2.82)
Negative Association
Positive Association
0.50 1.00 2.00
5.00 10.00 20.00
Odds Ratio
Odds ratios (ORs) for the binary outcomes of the metabolic syndrome and its component outcomes (diabetes mellitus, hypertension, increased triglyceride [TG] levels and decreased high-density lipoprotein cholesterol [HDL] levels, and general and abdominal obesity). The ORs are adjusted for age, sex, and smoking status. Whiskers indicate 95% confidence intervals.
TG, only the association for the population HS group was statistically significant. However, statistically significant differences in the TG levels between the hospital HS group and the non-HS group were found when we examined the continuous data. The hospital HS group had uniformly higher ORs than the population HS group. This result could indicate that differences in HS severity or the recent suggestion of different HS subtypes may play a part.26 This difference might also be an expression of a dilution of the population-based HS sample due to misclassification bias. The stronger ORs for the hospital HS group may also indicate detection bias; that is, HS patients within the hospital system are more likely to have been diagnosed with the outcome, which influences the self-reported diagnoses. However, detection bias was minimized by the inclusion of self-reported diagnosis and results of the physical examination and laboratory analysis of blood samples. When we examined the MetS components individually, the ORs for diabetes mellitus indicated a positive association, mainly due to type 2 diabetes mellitus. Quantification analysis demonstrated that nonfasting glucose level was 1% to 8% higher, and hemoglobin A1c level was 1% to 10% higher in the HS groups compared with the non-HS group. Previous studies have suggested that an approximately 1% reduction in hemoglobin A1c level may decrease the risk for myocardial infarction by 14% to 16%, indicating that the abnormalities seen in the HS patients have clinical significance.27 Further indirect support for this association is provided by the observation that metformin hydrochloride treatment may ameliorate HS.28
jamadermatology.com
JAMA Dermatology December 2014 Volume 150, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Purdue University User on 06/09/2015
1277
Research Original Investigation
Hidradenitis Suppurativa
Figure 2. Hidradenitis Suppurativa (HS) and the Components of the Metabolic Syndrome Hospital HS vs non-HS groups Population HS vs non-HS groups
Component
RM (95% CI)
Nonfasting blood glucose level
1.08 (1.02-1.15) 1.01 (0.99-1.03)
HbA1c level (IFCC)
1.10 (1.05-1.15) 1.01 (1.00-1.03)
Diastolic blood pressure
1.05 (1.01-1.10) 1.01 (1.00-1.02)
Systolic blood pressure
1.02 (0.97-1.07) 0.99 (0.98-1.01)
TG level
1.21 (1.00-1.46) 1.11 (1.04-1.17)
HDL level
0.88 (0.78-0.95) 0.90 (0.87-0.93)
LDL level
0.94 (0.84-1.06) 0.99 (0.96-1.03)
TC level
0.96 (0.90-1.06) 0.98 (0.96-1.00)
General obesity, BMI
1.21 (1.14-1.29) 1.09 (1.07-1.11)
Abdominal obesity, WC
1.14 (1.09-1.19) 1.07 (1.06-1.09)
Negative Association
0.80
Positive Association
1.00
1.20
1.40
1.60
Ratio of Means
Furthermore, the ORs for general and abdominal obesity were significant. When quantified, BMI was 9% to 21% greater, and WC was 7% to 14% larger in the HS groups than the non-HS group. Trimming of the WC by 4.4 cm from 102 cm (ie, a 4.3% reduction) may reduce the risk for diabetes mellitus by 58%, similarly indicating clinical relevance and a substantial potential for prevention in this generally neglected disease.29 The association of an atherogenic lipid profile (ie, increased TG levels and decreased HDL levels) was significant with regard to the decrease in HDL levels in both HS groups, but only significant with regard to the increase in TG levels in the population HS group. When quantified, the HS groups had an 11% to 21% higher TG level and a 10% to 14% lower HDL level than the non-HS group. A follow-up study of the effects of statins in 17 802 healthy individuals showed a significant reduction of cardiovascular events when TG levels were reduced by 17% and HDL levels were increased by 4%.30 Having hypertension was only significant with regard to the hospital HS group. When quantifying the hospital HS group, only the diastolic blood pressure was significantly increased by 5%. A recent meta-analysis of preventive treatment of hypertension suggested that lowering diastolic blood pressure from 90 to 85 mm Hg (ie, a 6% reduction) would reduce the risk for cardiovascular heart disease and stroke by approximately 20% and 30%, respectively.31 Our findings are in concordance with and expand the findings of 2 previous hospital-based studies.12,13 In aggregate, these data therefore suggest that the comorbidities of HS are clinically significant and that an increased clinical awareness of the 1278
Ratio of means (RMs) for continuous outcomes of the components of the metabolic syndrome (nonfasting blood glucose level, hemoglobin A1c [HbA1c] level, diastolic and systolic blood pressure, triglyceride [TG] blood level, high-density lipoprotein cholesterol [HDL] level, low-density lipoprotein cholesterol [LDL] level, total cholesterol [TC] level, general obesity, and abdominal obesity). The RMs are adjusted for age, sex, and smoking status. Whiskers indicate 95% confidence intervals. BMI indicates body mass index (calculated as weight in kilograms divided by height in meters squared); IFCC, International Federation of Clinical Chemistry; WC, waist circumference.
HS diagnosis and its comorbidities might be warranted in this potentially substantial group of patients. Obesity and inflammatory load were identified as possible confounders, partly but not exclusively explaining the associations and indicating a complex and overlapping relationship. Surprisingly, we found that physical activity level, diet and alcohol consumption, and the severity of HS did not influence the associations. The latter is in contrast to our supposition that the hospital HS group had higher ORs because of more severe disease, implying detection bias as previously discussed or an insufficiently sensitive measure of disease severity. Therefore, one can speculate that HS subtypes may influence the association with MetS more strongly than HS severity. The association of MetS has also been shown in the chronic generalized inflammatory disease rheumatoid arthritis and the skin disease psoriasis, for which the ORs for MetS are approximately 2.00 compared with almost 6.00 in HS.8 Furthermore, the associations in psoriasis have been suggested to be significant only with regard to a hospital-based HS cohort,8 implying that the burden of these comorbidities is greater for HS than for psoriasis. Therefore, the common etiological factors between inflammatory skin disease and MetS are more readily identified in HS than in psoriasis. The major strengths of our study are the large populationbased HS group and the inclusion of individuals with HS from hospital- and population-based groups. The broad recruitment reduced selection bias with a broader range of disease severities and thereby aided the generalization of the results. To explore misclassification bias of individuals with HS, we vali-
JAMA Dermatology December 2014 Volume 150, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Purdue University User on 06/09/2015
jamadermatology.com
Hidradenitis Suppurativa
Original Investigation Research
dated the HS definition with a sensitivity of 90% and a specificity of 97%.9 Because the self-reported questions used to identify HS patients refer to symptoms (ie, boils) rather than the actual diagnosis (ie, do you have HS?), we strove to optimize the inclusion of individuals with undiagnosed and misdiagnosed HS in the population, which is particularly pertinent for underdiagnosed diseases. The diagnosis of HS among hospitalized participants was physician verified. The combined methods of selfreporting, laboratory analysis of blood samples, and physical examination aimed to reduce false-negative findings with regard to the outcome (MetS). Finally, essential possible confounders were recognized and explored systematically. Potential limitations merit consideration. First, one must recognize that, because this study is cross-sectional, we cannot prove causality between HS and MetS. Furthermore, the population is suburban, most of the participants were white, and the group aged 20 to 30 years was underrepresented, which may limit the generalizability of our findings. In addition, an age bias was found between the HS and non-HS groups. However, we accommodated this age bias by age adjustments. The low participation rate of the hospital HS group increased varia-
ARTICLE INFORMATION Accepted for Publication: May 1, 2014. Published Online: September 17, 2014. doi:10.1001/jamadermatol.2014.1165. Author Contributions: Drs Miller and Jemec had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Miller, Ellervik, Vinding, Ibler, Jemec. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Miller, Ibler, Jemec. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Miller, Knudsen. Obtained funding: Miller, Ellervik, Jemec. Administrative, technical, or material support: Miller, Vinding, Ibler, Jemec. Study supervision: Ellervik, Ibler, Jemec. Conflict of Interest Disclosures: Dr Jemec has received consulting fees from Abbott Laboratories, AstraZeneca, MSD, Novartis, Pfizer, and DumexAlpharma; lecture fees from Abbott Laboratories, Galderma, Pfizer, and Roche; grant support from Abbott Laboratories, Pfizer, Photocure, and LEO Pharma; equipment on loan from Michelson Diagnostics; and reimbursement for travel expenses from Abbott Laboratories, Galderma, and Photocure. No other disclosures were reported.
tion and reduced power. The low participation rate may be an expression of the limited resources of HS patients due to the physical and mental burden of the disease. Nonfasting blood samples were used. However, differences in fasting and nonfasting lipid levels have been shown to be minimal.32 Furthermore, we did not include information on HS medical treatment, which might confound the results. Last, as with any questionnaire survey, the risk for recall bias was present.
Conclusions The data suggest an association between HS and the MetS in the hospital and population HS groups. This allegedly increased disease burden due to comorbidities indicates that HS patients require general medical attention beyond the skin. Future longitudinal studies with similar methods are needed to explore the temporal relationship of these associations. These studies should be large, include individuals with HS from the general population and hospital, and explore the differences between these groups and additional possible confounders.
of the grant supporting this study, was involved in analysis and interpretation of data and manuscript revision. The funding organizations had no other role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: Claus Bay, MSc Stat, Jørgen Iversen, BSc, and Torsten Skov, MD, PhD, Department of Biostatistics, LEO Pharma, provided statistical, technical, and epidemiological support. Birgitte Schnack Nielsen, clinical nutritionist, Department of Pediatrics, Roskilde Hospital, Denmark, provided information on diet. The contributors did not receive compensation. REFERENCES 1. Kurzen H, Kurokawa I, Jemec GB, et al. What causes hidradenitis suppurativa? Exp Dermatol. 2008;17(5):455-472. 2. Jemec GBE. Clinical practice: hidradenitis suppurativa. N Engl J Med. 2012;366(2):158-164. 3. Matusiak L, Bieniek A, Szepietowski JC. Psychophysical aspects of hidradenitis suppurativa. Acta Derm Venereol. 2010;90(3):264-268. 4. Esmann S, Jemec GBE. Psychosocial impact of hidradenitis suppurativa: a qualitative study. Acta Derm Venereol. 2011;91(3):328-332. 5. Jemec GBE, Heidenheim M, Nielsen NH. Hidradenitis suppurativa: characteristics and consequences. Clin Exp Dermatol. 1996;21(6):419-423.
suppurativa: results from two case-control studies. J Am Acad Dermatol. 2008;59(4):596-601. 9. Vinding GR, Miller IM, Zarchi K, et al. The prevalence of inverse recurrent suppuration: a population-based study of possible hidradenitis suppurativa. Br J Dermatol. 2014;170(4):884-889. 10. Jemec GBE, Heidenheim M, Nielsen NH. The prevalence of hidradenitis suppurativa and its potential precursor lesions. J Am Acad Dermatol. 1996;35(2, pt 1):191-194. 11. Vazquez BG, Alikhan A, Weaver AL, Wetter DA, Davis MD. Incidence of hidradenitis suppurativa and associated factors: a population-based study of Olmsted County, Minnesota. J Invest Dermatol. 2013; 133(1):97-103. 12. Sabat R, Chanwangpong A, Schneider-Burrus S, et al. Increased prevalence of metabolic syndrome in patients with acne inversa. PLoS One. 2012;7 (2):e31810. doi:10.1371/journal.pone.0031810. 13. Gold DA, Reeder VJ, Mahan MG, et al. The prevalence of metabolic syndrome in patients with hidradenitis suppurativa. J Am Acad Dermatol. 2014;70(4):699-703. 14. Miller IM, Ellervik C, Yazdanyar S, Jemec GB. Meta-analysis of psoriasis, cardiovascular disease, and associated risk factors. J Am Acad Dermatol. 2013;69(6):1014-1024. 15. Miller IM, Skaaby T, Ellervik C, Jemec GB. Quantifying cardiovascular disease risk factors in patients with psoriasis: a meta-analysis. Br J Dermatol. 2013;169(6):1180-1187.
Funding/Support: This study was supported by a grant under the Industrial PhD Programme and grants from the Danish Agency for Science, Technology, and Innovation and LEO Pharma (Dr Miller) and by the Jacob Madsen & Olga Madsens Foundation. The GESUS study was supported by the Johan and Lise Boserup Foundation, Trygfonden, Det Kommunale Momsfond, Johannes Fogs Foundation, Region Zealand Foundation, Næstved Hospital, Næstved Hospital Foundation, and the National Board of Health.
6. von der Werth JM, Williams HC. The natural history of hidradenitis suppurativa. J Eur Acad Dermatol Venereol. 2000;14(5):389-392.
16. Miller IM, Jemec GBE. Maturation of an idea: a historical perspective on the association of psoriasis with the metabolic syndrome and cardiovascular disease [letter]. Arch Dermatol. 2012;148(1):112.
7. Cosmatos I, Matcho A, Weinstein R, Montgomery MO, Stang P. Analysis of patient claims data to determine the prevalence of hidradenitis suppurativa in the United States. J Am Acad Dermatol. 2013;68(3):412-419.
17. Ferraz-Amaro I, González-Juanatey C, López-Mejias R, et al. Metabolic syndrome in rheumatoid arthritis. Mediators Inflamm. 2013; 2013:710928. doi:10.1155/2013/710928.
Role of the Funder/Sponsor: Dr Knudsen, who is an employee of LEO Pharma, which provided part
8. Revuz JE, Canoui-Poitrine F, Wolkenstein P, et al. Prevalence and factors associated with hidradenitis
jamadermatology.com
18. Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C; National Heart, Lung, and Blood
JAMA Dermatology December 2014 Volume 150, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Purdue University User on 06/09/2015
1279
Research Original Investigation
Hidradenitis Suppurativa
Institute; American Heart Association. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Arterioscler Thromb Vasc Biol. 2004;24(2):e13-e18. 19. Bergholdt HK, Bathum L, Kvetny J, et al. Study design, participation and characteristics of the Danish General Suburban Population Study. Dan Med J. 2013;60(9):A4693. 20. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285(19):2486-2497. 21. Alberti KG, Eckel RH, Grundy SM, et al; International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International
Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120(16):1640-1645.
27. Macisaac RJ, Jerums G. Intensive glucose control and cardiovascular outcomes in type 2 diabetes. Heart Lung Circ. 2011;20(10):647-654.
22. International Expert Committee. International Expert Committee report on the role of the A1c assay in the diagnosis of diabetes. Diabetes Care. 2009;32(7):1327-1334.
28. Verdolini R, Clayton N, Smith A, Alwash N, Mannello B. Metformin for the treatment of hidradenitis suppurativa: a little help along the way. J Eur Acad Dermatol Venereol. 2013;27(9):1101-1108.
23. Institute for Rational Pharmacotherapy in Denmark. Guidelines on diabetes. Månedsbladet rationel farmakoterapi. 2006;8. www.irf.dk. Accessed May 21, 2014.
29. Tuomilehto J, Lindström J, Eriksson JG, et al; Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344(18):1343-1350.
24. Chobanian AV, Bakris GL, Black HR, et al; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289(19):2560-2572. 25. Sartorius K, Lapins J, Emtestam L, Jemec GB. Suggestions for uniform outcome variables when reporting treatment effects in hidradenitis suppurativa. Br J Dermatol. 2003;149(1):211-213. 26. Canoui-Poitrine F, Le Thuaut A, Revuz JE, et al. Identification of three hidradenitis suppurativa phenotypes: latent class analysis of a cross-sectional study. J Invest Dermatol. 2013;133(6):1506-1511.
30. Ridker PM, Danielson E, Fonseca FA, et al; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21): 2195-2207. 31. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009;338:b1665. doi:10.1136/bmj.b1665. 32. Langsted A, Freiberg JJ, Nordestgaard BG. Fasting and nonfasting lipid levels: influence of normal food intake on lipids, lipoproteins, apolipoproteins, and cardiovascular risk prediction. Circulation. 2008;118(20):2047-2056.
NOTABLE NOTES
Apple of the Dermatologist’s Eye Deshan F. Sebaratnam, MBBS(Hons)
Dermatology is an intrinsically visual specialty, with pattern recognition a vital skill for clinical practice. It therefore follows that many of the classic descriptions of cutaneous pathologic abnormalities draw on parallels from the natural world, particularly the realm of botany. Trees, leaves, fruits, and flowers have all lent themselves to morphological descriptions over the centuries. The distribution of the papulosquamous plaques of pityriasis rosea has been compared to a fir tree and the hair shaft changes of trichorrhexis nodosa to bamboo. The figurate polycyclic plaques of erythema gyratum repens have been described as resembling wood grain and the jagged forked lesions of livedo racemosa tree branches.1 The induration associated with scleroderma is classically described as woody, and the neurofibromas of neurofibromatosis are said to have a rubbery consistency. Lichenification derives its name from lichen (a composite organism of fungi and algae living symbiotically), and the tumors of mycosis fungoides were initially thought to be fungal growths (though strictly speaking, the kingdom of Fungi is separate from that of plants). The ovate shape of the hypopigmented macules of tuberous sclerosis has been compared to ash leaves, and the color of Zoon balanitis has been described as resembling that of fallen autumn leaves. Fruits have inspired a range of dermatological descriptions, including peau d’orange, tapioca vesicles in pompholyx, and cayenne pepper spots in pigmented purpuric dermatoses. The berries are particularly well represented through strawberry birthmarks, mulberry xanthomas, and cherry angiomas.
1280
Flowers have also given rise to dermatological descriptions, such as the heliotrope rash of dermatomyositis, which originates from the lilac color of flowers of the genus Heliotropium.2 Perhaps the plant that has inspired the greatest number of wordsmiths within dermatology and beyond is the rose. Varicella zoster virus gives rise to “dew drops on a rose petal,” human herpes virus is associated with roseola infantum, and Salmonella typhi produces rose spots. The rosette is a well-recognized sign reported in a range of descriptions: clinically, as in linear IgA disease; dermoscopically, as in squamous cell carcinoma3; and pathologically, as in cylindromas. The visual nature of dermatology lends itself to comparisons between cutaneous pathological abnormalities and those seen in the botanical world, with several classical descriptions firmly “implanted” into the dermatological canon. Author Affiliation: Skin and Cancer Foundation Australia, Department of Dermatology, Westmead, NSW, Australia. Corresponding Author: Deshan F. Sebaratnam, Skin and Cancer Foundation Australia, 7 Ashley Lane, Westmead, NSW 2154, Australia ([email protected]). 1. Parsi K, Partsch H, Rabe E, Ramelet AA. Reticulate eruptions, part 2: historical perspectives, morphology, terminology and classification. Australas J Dermatol. 2011;52(4):237-244. 2. Russo T, Piccolo V, Ruocco E, Baroni A. The heliotrope sign of dermatomyositis: the correct meaning of the term heliotrope. Arch Dermatol. 2012;148(10):1178. 3. Rubegni P, Tataranno DR, Nami N, Fimiani M. Rosettes: optical effects and not dermoscopic patterns related to skin neoplasms. Australas J Dermatol. 2013;54(4):271-272.
JAMA Dermatology December 2014 Volume 150, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Purdue University User on 06/09/2015
jamadermatology.com
