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Increased prevalence of subclinical atherosclerosis in patients with hidradenitis suppurativa (HS)
ORIGINAL
ARTICLE
Increased prevalence of subclinical atherosclerosis in patients with hidradenitis suppurativa (HS) Marcos A. Gonzalez-L opez, MD, PhD,a Jose L. Hernandez, MD, PhD,b Marina Lacalle, MD,a e Cristina Mata, MD, Marıa L opez-Escobar, MD,a Raquel L opez-Mejıas, MD, PhD,c Virginia Portilla, BSc,c c Patricia Fuentevilla, BSc, Alfonso Corrales, MD, PhD,c M. Carmen Gonzalez-Vela, MD, PhD,d Miguel A. Gonzalez-Gay, MD, PhD,c and Ricardo Blanco, MD, PhDc Santander and Laredo, Cantabria, Spain Background: Chronic inflammatory diseases have been associated with increased prevalence of subclinical atherosclerosis. Hidradenitis suppurativa (HS) is a chronic inflammatory disease involving intertriginous skin. Objective: We sought to investigate the potential association between HS and subclinical atherosclerosis. Methods: This study included 68 patients with HS and 136 age- and sex-matched healthy control subjects. Patients with history of cardiovascular events, diabetes mellitus, chronic kidney disease, or another concomitant inflammatory condition were excluded. Carotid intima-media thickness and carotid plaques were measured by carotid ultrasonography. Adjustments were made for age, sex, and traditional cardiovascular risk factors. Results: Patients had greater carotid intima-media thickness values than control subjects (0.615 6 0.097 vs 0.578 6 0.098 mm; P = .012). Carotid plaques were also more frequent in patients than in control subjects (30.9% vs 22.1%). In the multivariable regression model adjusted for age, sex, and traditional cardiovascular risk factors, HS was significantly related to the presence of carotid plaques (odds ratio 2.99, 95% confidence interval 1.26-7.13; P = .013). Limitations: Causality could not be assessed. Conclusions: These results indicate an increased frequency of subclinical atherosclerosis in patients with HS. Accordingly, HS should be considered a disease associated with potentially increased cardiovascular risk. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2016.03.025.) Key words: cardiovascular disease; carotid intima-media thickness; carotid plaque; carotid ultrasonography; hidradenitis suppurativa; subclinical atherosclerosis.
idradenitis suppurativa (HS) or acne inversa is a chronic, inflammatory skin disease characterized by the formation of multiples abscesses, nodules, and scars in the apocrine glandbearing areas of the body. The most commonly
H
affected sites are the axillary, inguinal, perianal, gluteal, and submammary regions.1,2 The prevalence of this condition is estimated to be 1% to 4%.3-5 The etiopathogenesis of HS is not completely understood, although it is known that follicular occlusion,
From the Divisions of Dermatology,a Internal Medicine,b Rheumatology,c and Pathology,d Hospital Universitario Marques de Valdecilla, Instituto de Investigaci on Marques de Valdecilla, University of Cantabria, Santander; and Division of Rheumatology, Hospital Comarcal, Laredo,e Cantabria, Spain. Drs Gonzalez-Gay and Blanco share senior authorship. Supported by an unrestricted grant from Abbvie Inc. Disclosure: Dr Gonzalez-Gay received grant funding from Abbvie. Drs Gonzalez-L opez, Hernandez, Lacalle, Mata, L opez-Escobar, L opez-Mejıas, Corrales, Gonzalez-Vela, and Blanco, Ms Portilla, and Ms Fuentevilla have no conflicts of interest to declare. The
opinions expressed in this article are those of the authors and do not necessarily represent those of Abbvie Inc. Accepted for publication March 21, 2016. Reprint requests: Marcos A. Gonzalez-L opez, MD, PhD, Servicio de Dermatologıa, Hospital Universitario Marques de Valdecilla, Avda. de Valdecilla s/n, E-39008 Santander, Spain. E-mail: [email protected]. Published online June 8, 2016. 0190-9622/$36.00 Ó 2016 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2016.03.025
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as a result of hyperkeratosis, is the primary trigger.6 disease.21-27 Increased cIMT is an indicator of generalized atherosclerotic arterial disease. Carotid Several factors such as smoking, obesity, and horatherosclerosis is associated with coronary atheromonal imbalance may contribute to the histopathosclerosis and hence, the incidence of carotid plaque logical changes. Recent clinical and experimental or increased cIMT is higher in patients prone to studies have also demonstrated an important role of develop coronary artery disease.22,28 the immune system in the pathogenesis of HS.6,7 In this respect, some investigations have demonstrated In this study, we sought to investigate the potenenhanced concentrations of tial association between HS tumor necrosis factor-alfa in and subclinical atheroscleCAPSULE SUMMARY the serum of patients with rosis. For this purpose, we HS,8 and increased levels of compared the frequency of Chronic inflammatory diseases have subclinical atherosclerosis by this proinflammatory cytobeen associated with an increased measuring the cIMT and kine in HS skin have been prevalence of subclinical atherosclerosis. plaque formation between reported.9 In this respect, the Patients with hidradenitis suppurativa, patients with HS but without antietumor necrosis factormainly moderate and severe forms of the history of CVD, diabetes melalfa monoclonal antibody disease, have higher subclinical litus, chronic kidney disease, adalimumab has been shown atherosclerosis than control subjects. or concomitant inflammatory to improve HS,10,11 and it has Hidradenitis suppurativa should be disease and healthy control recently been approved for considered a disease associated with subjects. Moreover, we also use in this disease in the potentially increased cardiovascular risk. sought to assess whether United States. Epidemiologic data sugthere were clinical differgest that patients with HS ences between patients who have a higher comorbidity burden than the general have HS with and without carotid plaques. population.12-14 In this regard, it should be noted that recent studies have demonstrated a link between HS METHODS and metabolic syndrome, a multifaceted disorder Patients and control subjects associated with increased risk for subclinical atheroWe performed a cross-sectional case-control sclerosis and cardiovascular disease (CVD).15-18 study at the Hospital Universitario Marques de Furthermore, a recently reported systematic review Valdecilla (Santander, Spain). From February 2014 indicates that CVD risk factors appear at a signifito March 2015, consecutive Caucasian patients with cantly higher rate in patients with HS compared with an appropriate diagnosis of HS were recruited from control subjects.19 our dermatology outpatient clinic. The diagnosis of On the other hand, chronic inflammatory diseases HS was made by dermatologists. Diagnostic criteria such as rheumatoid arthritis,20 ankylosing spondywere established as follows, and all 3 criteria were litis,21 psoriasis without joint involvement,22-26 and necessary to establish the diagnosis: (1) presence of psoriatic arthritis27 have been associated with an typical lesions: nodules (inflammatory or noninflamincreased prevalence of subclinical atherosclerosis. matory), abscesses, fistula/sinus (exudative or The premature and accelerated development of nonexudative), scars, or a combination of these; (2) atherosclerotic disease in these inflammatory disorinvolvement of typical areas: the axillary, inguinal, ders has been related to the chronic inflammation inframammary, and anogenital regions; and (3) an overload and the additive effect of traditional CVD evolving course with relapses and chronicity. risk factors.23 In this regard, HS has been associated Patients with any 1 of the following were excluded: with various systemic inflammatory conditions such (1) documented history of CVD, including ischemic as arthritis, spondyloarthropathy, and inflammatory heart disease, heart failure, cerebrovascular bowel disease.13 accidents, or peripheral arterial disease; (2) type 1 Currently, there are a number of noninvasive, or type 2 diabetes mellitus; (3) chronic kidney easy to interpret, validated tools that have been disease (serum creatinine values in all individuals found useful to disclose the presence of subclinical included in the study had to be \1.3 mg/dL); and (4) atherosclerosis in patients with chronic inflammatory presence of concomitant inflammatory diseases such diseases.24 Thus, the measurement of carotid as inflammatory bowel disease, inflammatory intima-media thickness (cIMT) and plaque by carotid arthritis (rheumatoid arthritis or spondyloarthropultrasound is an accepted surrogate marker for athy), connective tissue diseases (systemic lupus macrovascular atherosclerosis that provides early erythematosus or other autoimmune diseases), or vascular information in subclinical stages of the cutaneous inflammatory diseases (psoriasis or atopic d
d
d
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Abbreviations used: BMI: BP: cIMT: CVD: HDL-c: HS: LDL-c: PGA:
body mass index blood pressure carotid intima-media thickness cardiovascular disease high-density lipoprotein cholesterol hidradenitis suppurativa low-density lipoprotein cholesterol Physician Global Assessment
dermatitis among others). Among the 81 screened patients with HS, 5 had diabetes mellitus and 8 had a documented history of CVD. As a result, a total of 68 patients with HS were finally recruited. Control subjects (n = 136) were communitybased. They were recruited by general practitioners of the Cantabria region. None of the control subjects had a history of inflammatory disease, CVD, diabetes mellitus, or chronic kidney disease. The local institutional ethics committee approved the protocol of the study, which was performed according to the Declaration of Helsinki. Also, written informed consent was obtained from all participants. Clinical examination and cardiovascular risk assessment A clinical examination of all patients with HS was carried out. The severity of HS was assessed by the HS Physician Global Assessment (PGA), which includes 6 stages (scale 0-5) with clear guidance for disease severity assessment (Table I).11 According to HS-PGA, HS was classified as moderate-severe-very severe when HS-PGA score was 3 or more. The Hurley grade of disease severity for each zone involved at the time of clinical examination was also evaluated.29 Disease severity was assessed by 2 dermatologists (M. A. G.-L. and M. L.-E.) in all the cases. Moreover, information on disease duration was also assessed in all patients. Patients and control subjects were interviewed about data of early cardiovascular events in firstdegree relatives and history of traditional CVD risk factors: hypertension (defined as a systolic blood pressure [BP] $140 mm Hg, diastolic BP $90 mm Hg, or the use of antihypertensive agents), hyperlipidemia (defined as total cholesterol and/or triglyceride levels in fasting plasma [200 mg/dL and/or [150 mg/dL, respectively, or prescription of lipidlowering medication), and history of smoking. Data on current and prior systemic therapy for HS were also registered. Body height and weight, body mass index (BMI), systolic BP, and diastolic BP were measured in all patients and control subjects at the time of the study.
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Laboratory assessment Venous blood samples were drawn after an overnight fast in all participants, and analyzed for total cholesterol, high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), triglycerides, glucose, high-sensitivity C-reactive protein, and erythrocyte sedimentation rate. Carotid ultrasonographic study Carotid ultrasound examination included the measurement of cIMT in the common carotid artery and the detection of focal plaques in the extracranial carotid tree. The study was performed using a commercially available scanner (Mylab 70 Esaote, Genoa, Italy) equipped with a 7 to 12 MHz linear transducer and the automated software-guided technique radiofrequencydQuality Intima Media Thickness in real-time (QIMT, Esaote, Maastricht, The Netherlands). Patients and control subjects were in a supine position during the examination and carotid arteries were scanned cross-sectionally and longitudinally. Carotid atherosclerotic plaque was identified as recommended in the Mannheim consensus: a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding cIMT value or demonstrates a thickness of greater than 1.5 mm as measured from the media-adventitia interface of the intima-lumen interface.30 Statistical analysis Results were reported as mean 6 SD, median and interquartile range, or proportions as appropriate. Quantitative variables were compared by the Student t test or Mann-Whitney U test as appropriate. Pearson x2 test or Fisher exact test were used to compare qualitative variables. Correlation analyses were performed separately in patients and control subjects using Pearson correlation coefficient or Spearman rho when appropriate. A backward stepwise multivariable linear regression analysis adjusted for age, sex, BP, serum LDL-c and HDL-c, current smoking, and BMI was performed to ascertain whether HS was associated with cIMT. In addition, an adjusted backward stepwise multivariable logistic regression analysis was performed to assess whether HS was related to carotid plaque measured by ultrasonography. A significance level of 5% was used. Software (STATA 12/SE, StataCorp, College Station, TX) was used in all the calculations.
RESULTS Demographic, clinical, and laboratory data A total of 68 patients with HS and 136 healthy control subjects were studied. The main demographic
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Table I. Hidradenitis suppurativa Physician Global Assessment Clear (score = 0) Minimal (score = 1) Mild (score = 2) Moderate (score = 3) Severe (score = 4) Very severe (score = 5)
No abscesses, no draining fistulae, no inflammatory nodules, and no noninflammatory nodules No abscesses, no draining fistulae, no inflammatory nodules, but presence of noninflammatory nodules No abscesses, no draining fistulae, and 1-4 inflammatory nodules, or 1 abscess or draining fistula and no inflammatory nodules No abscesses, no draining fistulae, $5 inflammatory nodules, and $1 inflammatory nodule, or 2-5 abscesses or draining fistula and \10 inflammatory nodules 2-5 Abscesses or draining fistula and [10 inflammatory nodules [5 Abscesses or draining fistula
Table II. Demographic, clinical, and laboratory findings of patients with hidradenitis suppurativa and healthy control subjects Variable
Age, y, mean 6 SD Men/women, n Disease duration at study onset, mean 6 SD HS-PGA score, 0-5 scale, n (%) Minimal, mild [\3] Moderate/severe/very severe [$3] Hurley stage, n (%) I II III History of classic cardiovascular risk factors, n (%) Current smokers Obesity Hyperlipidemia Hypertension Family history of early cardiovascular events, n (%) BMI, kg/m2, mean 6 SD Systolic BP, mm Hg, mean 6 SD Diastolic BP, mm Hg, mean 6 SD Total cholesterol, mg/dL, mean 6 SD LDL-c, mg/dL, mean 6 SD HDL-c, mg/dL, mean 6 SD Triglycerides, mg/dL, mean 6 SD Glucose, mg/dL, mean 6 SD ESR, mm/first h, median (IQR) hs-CRP, mg/L, median (IQR)
HS, n = 68
Control, n = 136
P
42.4 6 11.9 30/38 17.5 6 11.1
42.9 6 11.3 57/79 e
.72 .77
39 (57.4) 29 (42.6)
e e
e e
19 (28.0) 37 (54.4) 12 (17.6)
e e e
e e e
36 (26.5) 23 (17.2) 26 (19.1) 17 (12.5) 16 (11.9) 25.9 6 4.9 124.7 6 16.6 78.0 6 9.7 201.4 6 39.7 121.3 6 35.9 60.2 6 16.8 100.6 6 56.2 86.5 6 12.5 4.5 (2.0-8.0) 0.80 (0.50-2.00)
\.0001 \.0001 .33 .52 .82 \.0001 .006 .11 .004 .24 \.0001 .47 \.0001 \.0001 \.0001
43 (63.2) 28 (41.2) 9 (13.2) 11 (16.2) 9 (13.2) 29.0 6 5.2 131.5 6 16.2 80.3 6 9.2 185.1 6 33.0 115.2 6 32.2 50.5 6 16.1 95.4 6 44.9 94.3 6 12.3 13.0 (5.3-22.0) 3.40 (1.43-7.20)
BMI, Body mass index; BP, blood pressure; ESR, erythrocyte sedimentation rate; HDL-c, high-density lipoprotein cholesterol; HS, hidradenitis suppurativa; hs-CRP, high-sensitivity C-reactive protein; LDL-c, low-density lipoprotein cholesterol; PGA, Physician Global Assessment.
and clinical characteristics are summarized in Table II. The mean age did not significantly differ between the patients with HS and control subjects. The gender distribution for both groups was similar. According to the HS-PGA, 29 patients (42.6%) were classified as having minimal-mild HS (HS-PGA score \3) and the remaining 39 (57.4%) as having moderate-severe/very
severe HS (HS-PGA score $3). The mean duration of HS was 17.5 6 11.1 years (median 16.5 [interquartile range 8.3-25.0] years). There were no significant differences in the overall prevalence of hypertension and dyslipidemia between patients and control subjects. However, when compared with the control group, patients
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with HS were significantly more likely to be obese and smokers, and had higher BMI and systolic BP (Table II). Fasting plasma glucose levels, serum high-sensitivity C-reactive protein, and erythrocyte sedimentation rate were higher in patients than in control subjects, whereas serum HDL-c was significantly lower in patients with HS than in the control group (Table II). Carotid ultrasound findings Patients with HS had a significantly greater cIMT than control subjects (0.615 6 0.097 vs 0.578 6 0.098 mm; P = .012). In the linear regression multivariable analysis, after adjusting for age, sex, systolic BP, serum LDL-c and HDL-c levels, current smoking, and BMI, HS remained as a significant factor for higher cIMT (adjusted beta coefficient = 0.136; P = .011). The inclusion of additional variables to the regression model (serum glucose or triglyceride levels, diastolic BP) did not change this association. Carotid plaques were also more common in patients with HS (30.9%) than in control subjects (22.1%), but the difference was not statistically significant (P = .17). Nevertheless, we observed a significantly higher frequency of carotid plaques in the subgroup of patients with HS and moderatesevere/very severe disease (HS-PGA score $3; n = 39) when compared with control subjects (41% vs 22.1%; P = .023). In the logistic multivariable regression model adjusted for age, sex, systolic BP, serum LDL-c and HDL-c levels, current smoking, and BMI, HS was significantly related to the presence of carotid plaques (odds ratio 2.99, 95% confidence interval 1.26-7.13; P = .013). The inclusion of additional variables to the regression model (cIMT, serum glucose or triglyceride levels, diastolic BP) did not change this association. Correlation between cIMT and clinical variables in patients with HS A strong positive correlation was observed between the cIMT of patients with HS and age at the time of diagnosis (r = 0.615, P \ .0001) and disease duration (r = 0.453, P \ .0001). Significant correlation between cIMT and systolic BP (r = 0.331, P = .006) and fasting glucose levels (r = 0.331, P = .006) was also found (Table III). Differences between patients who have HS with and without plaques To further investigate the severity of the macrovascular atherosclerotic disease in patients with HS without clinically evident cardiovascular complications, we aimed to determine whether there were
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Table III. Correlation between carotid intimamedia thickness and clinical variables in patients with hidradenitis suppurativa cIMT Variable
Age, y Sex, female Disease duration, y HS-PGA score, $3 BMI, kg/m2 Current smoker, yes Systolic BP, mm Hg Diastolic BP, mm Hg Total cholesterol, mg/dL HDL-c, mg/dL LDL-c, mg/dL Triglycerides, mg/dL Fasting glucose, mg/dL hs-CRP, g/L ESR, mm/first h
r
0.6155 0.504 0.453 0.201 0.148 0.081 0.331 0.132 0.168 0.160 0.209 0.186 0.331 0.160 0.194
P
\.0001 \.0001 \.0001 .10 .22 .51 .006 .28 .17 .19 .08 .13 .006 .19 .11
BMI, Body mass index; BP, blood pressure; ESR, erythrocyte sedimentation rate; HDL-c, high-density lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; LDL-c, low-density lipoprotein cholesterol.
some clinical differences between patients who have HS with and without carotid plaques (Table IV). At the time of the study, the patients with plaques were older and had a significantly longer disease duration. They had more commonly severe forms of HS (HS-PGA score $3 and Hurley III stage) and were more frequently current smokers than patients with HS without carotid plaques. No statistical differences between patients who have HS with or without plaques according to sex, fasting glucose, HDL-c and LDL-c, or systolic BP and diastolic BP at the time of the study were observed. The cIMT values were significantly higher in patients with plaques than those without (0.653 6 0.107 vs 0.598 6 0.087 mm; P = .03) (Table IV).
DISCUSSION The results of this study show that patients with HS without clinically evident CVD have a higher prevalence of subclinical atherosclerosis by exhibiting a greater cIMT than control subjects matched for age and sex. Carotid plaques were also more frequently observed in patients with HS than in control subjects. However, this difference was only statistically significant between the subgroup of patients with moderate-severe/very severe HS (HS-PGA score $3) and the control group. In fact, we have found that the presence of carotid plaques are 3-fold more frequent in this subgroup of patients with HS compared with matched control subjects.
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Table IV. Main clinical and ultrasonographic differences between patients who have hidradenitis suppurativa with and without carotid plaques Variable
Age, y, mean 6 SD Men/women, n Age at disease onset, y Disease duration at time of study, y, mean 6 SD HS-PGA score moderate/severe/very severe [$3], n (%) Hurley stage, n (%) I II III BMI, kg/m2, mean 6 SD Normal \25 n (%) Overweight 25-29.9 n (%) Obese [30 n (%) Smoking status, n (%) Current Former Systolic BP, mm Hg, mean 6 SD Diastolic BP, mm Hg, mean 6 SD Total cholesterol, mg/dL, mean 6 SD HDL-c, mg/dL, mean 6 SD LDL-c, mg/dL, mean 6 SD Triglycerides, mg/dL, mean 6 SD Fasting glucose, mg/dL, mean 6 SD cIMT, mm, mean 6 SD
With plaques, n = 21
Without plaques, n = 47
P
49 6 9 8/13 25.3 6 12.9 23.4 6 9.8 16 (76.2)
38 6 12 22/25 24.3 6 9.8 14.9 6 10.8 23 (48.9)
.001 .60 .74 .003 .04
3 (14.3) 11 (52.4) 7 (33.3) 28.9 6 4.6 4 (19.0) 10 (47.6) 7 (33.4)
16 (34.0) 26 (55.3) 5 (10.7) 29.1 6 5.6 11 (23.4) 15 (31.9) 21 (44.7)
.07 .96 .03 .89 .76 .53 .38
17 (81) 4 (19.0) 135.3 6 17.5 81.1 6 9.4 191.2 6 34.2 50.6 6 17.9 120.1 6 35.6 98.7 6 38.2 95.4 6 13.9 0.653 6 0.107
26 (55.3) 14 (29.8) 129.8 6 9.4 8.0 6 9.3 182.5 6 32.6 50.6 6 15.4 112.7 6 30.7 93.9 6 47.9 93.8 6 11.7 0.598 6 0.087
.04 .55 .20 .67 .32 .99 .33 .69 .62 .03
BMI, Body mass index; BP, blood pressure; cIMT, carotid intima-media thickness; HDL-c, high-density lipoprotein cholesterol; HS, hidradenitis suppurativa; LDL-c, low-density lipoprotein cholesterol; PGA, Physician Global Assessment.
The formation of carotid plaques is considered a later step in the atherogenesis process and it is more strongly associated with an increased risk of CVD compared with increased cIMT.28,31 However, cIMT has also been shown to be independently associated with an increased risk for both coronary artery disease and stroke.28,31 The mechanism by which premature atherosclerosis develops in patients with HS remains to be clarified. A possible explanation would be that the higher prevalence of traditional CVD risk factors in patients with HS, such as increased smoking and obesity, could contribute to accelerated atherosclerosis. However, in our study the difference in cIMT between the patients with HS and control subjects remained significant after adjusting for these potential confounding risk factors. This suggests that HS itself, like other chronic inflammatory diseases, may be an independent risk factor for atherosclerosis, regardless of the presence of classic CVD risk factors. In this sense, the strong correlation between the disease duration of HS and cIMT detected in this study may suggest that a persistent chronic inflammation linked to HS may be of major importance to explain the accelerated atherogenesis.
These results are in agreement with various studies performed in patients with psoriasis that showed a correlation of abnormally increased cIMT with the duration of psoriasis.22,32,33 In keeping with that, our study also revealed a correlation of the disease with HS severity. In this regard, carotid plaques were more commonly observed in patients with HS who had longer disease duration and more severe forms of the disease. The mechanism of atherogenicity caused by inflammation is complex, although increasing evidence supports an important role for the inflammatory process in all phases of atherosclerosis.34 It is known that chronic and systemic inflammation may damage the vascular endothelium, and impaired endothelial function is an early step in the atherosclerosis process.21 In this regard, the inflammatory cells and the proinflammatory cytokines implicated in the chronic inflammation observed in HS may also promote the development of endothelial cell dysfunction and the subsequent development of accelerated atherogenesis. Our study has the inherent limitations of its cross-sectional design, mainly the inability to establish probable causality.
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In conclusion, we have showed that patients with HS have an increased prevalence of subclinical atherosclerosis that is independent of classic CV risk factors compared with control subjects. Clinicians should pay attention to controlling traditional atherosclerotic CVD risk factors in patients with HS in an attempt to reduce the cardiovascular mortality and morbidity in these patients. REFERENCES 1. Revuz J. Hidradenitis suppurativa. J Eur Acad Dermatol Venereol. 2009;23:985-988. 2. Jemec GB. Clinical practice. Hidradenitis suppurativa. N Engl J Med. 2012;366:158-164. 3. Jemec GB, 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. 4. Revuz JE, Canoui-Poitrine F, Wolkenstein P, et al. Prevalence and factors associated with hidradenitis suppurativa: results from two case-control studies. J Am Acad Dermatol. 2008;59:596-601. 5. 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;68:412-429. 6. Prens E, Deckers I. Pathophysiology of hidradenitis suppurativa: an update. J Am Acad Dermatol. 2015;73(5 Suppl 1):S8-S11. 7. Kelly G, Sweeney CM, Tobin AM, Kirby B. Hidradenitis suppurativa: the role of immune dysregulation. Int J Dermatol. 2014;53:1186-1196. 8. Matusiak L, Bieniek A, Szepietowski JC. Increased serum tumor necrosis factor-alpha in hidradenitis suppurativa patients: is there a basis for treatment with anti-tumor necrosis factor-alpha agents? Acta Derm Venereol. 2009;89:601-603. 9. van der Zee HH, de Ruiter L, van den Broecke DG, Dik WA, Laman JD, Prens EP. Elevated levels of tumor necrosis factor (TNF)-a, interleukin (IL)-1b and IL-10 in hidradenitis suppurativa skin: a rationale for targeting TNF-a and IL-1b. Br J Dermatol. 2011;164:1292-1298. 10. Blanco R, Martınez-Taboada VM, Villa I, et al. Long-term successful adalimumab therapy in severe hidradenitis suppurativa. Arch Dermatol. 2009;145:580-584. 11. Kimball AB, Kerdel F, Adams D, et al. Adalimumab for the treatment of moderate to severe hidradenitis suppurativa: a parallel randomized trial. Ann Intern Med. 2012;157:846-855. 12. Shlyankevich J, Chen AJ, Kim GE, Kimball AB. Hidradenitis suppurativa is a systemic disease with substantial comorbidity burden: a chart-verified case-control analysis. J Am Acad Dermatol. 2014;71:1144-1150. 13. Kohorst JJ, Kimball AB, Davis MD. Systemic associations of hidradenitis suppurativa. J Am Acad Dermatol. 2015;73(5 Suppl 1):S27-S35. 14. Fimmel S, Zouboulis CC. Comorbidities of hidradenitis suppurativa (acne inversa). Dermatoendocrinol. 2010;2:9-16. 15. Sabat R, Chanwangpong A, Schneider-Burrus S, et al. Increased prevalence of metabolic syndrome in patients with acne inversa. PLoS One. 2012;7:e31810. 16. Gold DA, Reeder VJ, Mahan MG, Hamzavi IH. The prevalence of metabolic syndrome in patients with hidradenitis suppurativa. J Am Acad Dermatol. 2014;70(4):699-703. 17. Miller IM, Ellervik C, Vinding GR, et al. Association of metabolic syndrome and hidradenitis suppurativa. JAMA Dermatol. 2014; 150:1273-1280. 18. Shalom G, Freud T, Harman-Boehm I, Polishchuk I, Cohen AD. Hidradenitis suppurativa and metabolic
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syndrome: a comparative cross-sectional study of 3207 patients. Br J Dermatol. 2015;173:464-470. Tzellos T, Zouboulis CC, Gulliver W, Cohen AD, Wolkenstein P, Jemec GB. Cardiovascular disease risk factors in patients with hidradenitis suppurativa: a systematic review and meta-analysis of observational studies. Br J Dermatol. 2015;173(5):1142-1155. Gonzalez-Juanatey C, Llorca J, Testa A, Revuelta J, Garcia-Porrua C, Gonzalez-Gay MA. Increased prevalence of severe subclinical atherosclerotic findings in long-term treated rheumatoid arthritis patients without clinically evident atherosclerotic disease. Medicine (Baltimore). 2003;82:407-413. Gonzalez-Juanatey C, Vazquez-Rodriguez TR, MirandaFilloy JA, et al. The high prevalence of subclinical atherosclerosis in patients with ankylosing spondylitis without clinically evident cardiovascular disease. Medicine (Baltimore). 2009;88: 358-365. El-Mongy S, Fathy H, Abdelaziz A, et al. Subclinical atherosclerosis in patients with chronic psoriasis: a potential association. J Eur Acad Dermatol Venereol. 2010;24:661-666. Gonzalez-Gay MA, Gonzalez-Vela C, Gonzalez-Juanatey C. Psoriasis: a skin disease associated with increased cardiovascular risk. Actas Dermosifiliogr. 2012;103:595-598. Kerekes G, Soltesz P, Nurmohamed MT, et al. Validated methods for assessment of subclinical atherosclerosis in rheumatology. Nat Rev Rheumatol. 2012;8:224-234. Evensen K, Slevolden E, Skagen K, et al. Increased subclinical atherosclerosis in patients with chronic plaque psoriasis. Atherosclerosis. 2014;237:499-503. Robati RM, Partovi-Kia M, Haghighatkhah HR, Younespour S, Abdollahimajd F. Increased serum leptin and resistin levels and increased carotid intima-media wall thickness in patients with psoriasis: is psoriasis associated with atherosclerosis? J Am Acad Dermatol. 2014;71:642-648. Gonzalez-Juanatey C, Llorca J, Amigo-Diaz E, Dierssen T, Martin J, Gonzalez-Gay MA. High prevalence of subclinical atherosclerosis in psoriatic arthritis patients without clinically evident cardiovascular disease or classic atherosclerosis risk factors. Arthritis Rheum. 2007;57:1074-1080. Celermajer DS, Sorensen KE, Gooch VM, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992;340:1111-1115. Hurley H. Axillary hyperhidrosis, apocrine bromhidrosis, hidradenitis suppurativa and familial benign pemphigus: surgical approach. In: Roenigk RK, Roenigk HH, eds. Roenigk and Roenigks dermatologic surgery principles and practice. New York (NY): Marcel Dekker Inc; 1989:623-645. Touboul PJ, Hennerici MG, Meairs S, et al. Mannheim carotid intima-media thickness consensus (2004-2006). An update on behalf of the Advisory Board of the 3rd and 4th Watching the Risk Symposium, 13th and 15th European Stroke Conferences, Mannheim, Germany, 2004, and Brussels, Belgium, 2006. Cerebrovasc Dis. 2007;23:75-80. O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med. 1999;340:14-22. Enany B, El Zohiery AK, Elhilaly R, Badr T. Carotid intima-media thickness and serum leptin in psoriasis. Herz. 2012;37:527-533. Elsheikh RG, Amin Tel-S, El-Ashmawy AA, Abdalla SI. Evaluation of subclinical atherosclerosis in Egyptian psoriatic patients. J Saudi Heart Assoc. 2014;26:63-71. Sp€ah F. Inflammation in atherosclerosis and psoriasis: common pathogenic mechanisms and the potential for an integrated treatment approach. Br J Dermatol. 2008; 159(Suppl):10-17.
ARTICLE
Increased prevalence of subclinical atherosclerosis in patients with hidradenitis suppurativa (HS) Marcos A. Gonzalez-L opez, MD, PhD,a Jose L. Hernandez, MD, PhD,b Marina Lacalle, MD,a e Cristina Mata, MD, Marıa L opez-Escobar, MD,a Raquel L opez-Mejıas, MD, PhD,c Virginia Portilla, BSc,c c Patricia Fuentevilla, BSc, Alfonso Corrales, MD, PhD,c M. Carmen Gonzalez-Vela, MD, PhD,d Miguel A. Gonzalez-Gay, MD, PhD,c and Ricardo Blanco, MD, PhDc Santander and Laredo, Cantabria, Spain Background: Chronic inflammatory diseases have been associated with increased prevalence of subclinical atherosclerosis. Hidradenitis suppurativa (HS) is a chronic inflammatory disease involving intertriginous skin. Objective: We sought to investigate the potential association between HS and subclinical atherosclerosis. Methods: This study included 68 patients with HS and 136 age- and sex-matched healthy control subjects. Patients with history of cardiovascular events, diabetes mellitus, chronic kidney disease, or another concomitant inflammatory condition were excluded. Carotid intima-media thickness and carotid plaques were measured by carotid ultrasonography. Adjustments were made for age, sex, and traditional cardiovascular risk factors. Results: Patients had greater carotid intima-media thickness values than control subjects (0.615 6 0.097 vs 0.578 6 0.098 mm; P = .012). Carotid plaques were also more frequent in patients than in control subjects (30.9% vs 22.1%). In the multivariable regression model adjusted for age, sex, and traditional cardiovascular risk factors, HS was significantly related to the presence of carotid plaques (odds ratio 2.99, 95% confidence interval 1.26-7.13; P = .013). Limitations: Causality could not be assessed. Conclusions: These results indicate an increased frequency of subclinical atherosclerosis in patients with HS. Accordingly, HS should be considered a disease associated with potentially increased cardiovascular risk. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2016.03.025.) Key words: cardiovascular disease; carotid intima-media thickness; carotid plaque; carotid ultrasonography; hidradenitis suppurativa; subclinical atherosclerosis.
idradenitis suppurativa (HS) or acne inversa is a chronic, inflammatory skin disease characterized by the formation of multiples abscesses, nodules, and scars in the apocrine glandbearing areas of the body. The most commonly
H
affected sites are the axillary, inguinal, perianal, gluteal, and submammary regions.1,2 The prevalence of this condition is estimated to be 1% to 4%.3-5 The etiopathogenesis of HS is not completely understood, although it is known that follicular occlusion,
From the Divisions of Dermatology,a Internal Medicine,b Rheumatology,c and Pathology,d Hospital Universitario Marques de Valdecilla, Instituto de Investigaci on Marques de Valdecilla, University of Cantabria, Santander; and Division of Rheumatology, Hospital Comarcal, Laredo,e Cantabria, Spain. Drs Gonzalez-Gay and Blanco share senior authorship. Supported by an unrestricted grant from Abbvie Inc. Disclosure: Dr Gonzalez-Gay received grant funding from Abbvie. Drs Gonzalez-L opez, Hernandez, Lacalle, Mata, L opez-Escobar, L opez-Mejıas, Corrales, Gonzalez-Vela, and Blanco, Ms Portilla, and Ms Fuentevilla have no conflicts of interest to declare. The
opinions expressed in this article are those of the authors and do not necessarily represent those of Abbvie Inc. Accepted for publication March 21, 2016. Reprint requests: Marcos A. Gonzalez-L opez, MD, PhD, Servicio de Dermatologıa, Hospital Universitario Marques de Valdecilla, Avda. de Valdecilla s/n, E-39008 Santander, Spain. E-mail: [email protected]. Published online June 8, 2016. 0190-9622/$36.00 Ó 2016 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2016.03.025
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as a result of hyperkeratosis, is the primary trigger.6 disease.21-27 Increased cIMT is an indicator of generalized atherosclerotic arterial disease. Carotid Several factors such as smoking, obesity, and horatherosclerosis is associated with coronary atheromonal imbalance may contribute to the histopathosclerosis and hence, the incidence of carotid plaque logical changes. Recent clinical and experimental or increased cIMT is higher in patients prone to studies have also demonstrated an important role of develop coronary artery disease.22,28 the immune system in the pathogenesis of HS.6,7 In this respect, some investigations have demonstrated In this study, we sought to investigate the potenenhanced concentrations of tial association between HS tumor necrosis factor-alfa in and subclinical atheroscleCAPSULE SUMMARY the serum of patients with rosis. For this purpose, we HS,8 and increased levels of compared the frequency of Chronic inflammatory diseases have subclinical atherosclerosis by this proinflammatory cytobeen associated with an increased measuring the cIMT and kine in HS skin have been prevalence of subclinical atherosclerosis. plaque formation between reported.9 In this respect, the Patients with hidradenitis suppurativa, patients with HS but without antietumor necrosis factormainly moderate and severe forms of the history of CVD, diabetes melalfa monoclonal antibody disease, have higher subclinical litus, chronic kidney disease, adalimumab has been shown atherosclerosis than control subjects. or concomitant inflammatory to improve HS,10,11 and it has Hidradenitis suppurativa should be disease and healthy control recently been approved for considered a disease associated with subjects. Moreover, we also use in this disease in the potentially increased cardiovascular risk. sought to assess whether United States. Epidemiologic data sugthere were clinical differgest that patients with HS ences between patients who have a higher comorbidity burden than the general have HS with and without carotid plaques. population.12-14 In this regard, it should be noted that recent studies have demonstrated a link between HS METHODS and metabolic syndrome, a multifaceted disorder Patients and control subjects associated with increased risk for subclinical atheroWe performed a cross-sectional case-control sclerosis and cardiovascular disease (CVD).15-18 study at the Hospital Universitario Marques de Furthermore, a recently reported systematic review Valdecilla (Santander, Spain). From February 2014 indicates that CVD risk factors appear at a signifito March 2015, consecutive Caucasian patients with cantly higher rate in patients with HS compared with an appropriate diagnosis of HS were recruited from control subjects.19 our dermatology outpatient clinic. The diagnosis of On the other hand, chronic inflammatory diseases HS was made by dermatologists. Diagnostic criteria such as rheumatoid arthritis,20 ankylosing spondywere established as follows, and all 3 criteria were litis,21 psoriasis without joint involvement,22-26 and necessary to establish the diagnosis: (1) presence of psoriatic arthritis27 have been associated with an typical lesions: nodules (inflammatory or noninflamincreased prevalence of subclinical atherosclerosis. matory), abscesses, fistula/sinus (exudative or The premature and accelerated development of nonexudative), scars, or a combination of these; (2) atherosclerotic disease in these inflammatory disorinvolvement of typical areas: the axillary, inguinal, ders has been related to the chronic inflammation inframammary, and anogenital regions; and (3) an overload and the additive effect of traditional CVD evolving course with relapses and chronicity. risk factors.23 In this regard, HS has been associated Patients with any 1 of the following were excluded: with various systemic inflammatory conditions such (1) documented history of CVD, including ischemic as arthritis, spondyloarthropathy, and inflammatory heart disease, heart failure, cerebrovascular bowel disease.13 accidents, or peripheral arterial disease; (2) type 1 Currently, there are a number of noninvasive, or type 2 diabetes mellitus; (3) chronic kidney easy to interpret, validated tools that have been disease (serum creatinine values in all individuals found useful to disclose the presence of subclinical included in the study had to be \1.3 mg/dL); and (4) atherosclerosis in patients with chronic inflammatory presence of concomitant inflammatory diseases such diseases.24 Thus, the measurement of carotid as inflammatory bowel disease, inflammatory intima-media thickness (cIMT) and plaque by carotid arthritis (rheumatoid arthritis or spondyloarthropultrasound is an accepted surrogate marker for athy), connective tissue diseases (systemic lupus macrovascular atherosclerosis that provides early erythematosus or other autoimmune diseases), or vascular information in subclinical stages of the cutaneous inflammatory diseases (psoriasis or atopic d
d
d
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Abbreviations used: BMI: BP: cIMT: CVD: HDL-c: HS: LDL-c: PGA:
body mass index blood pressure carotid intima-media thickness cardiovascular disease high-density lipoprotein cholesterol hidradenitis suppurativa low-density lipoprotein cholesterol Physician Global Assessment
dermatitis among others). Among the 81 screened patients with HS, 5 had diabetes mellitus and 8 had a documented history of CVD. As a result, a total of 68 patients with HS were finally recruited. Control subjects (n = 136) were communitybased. They were recruited by general practitioners of the Cantabria region. None of the control subjects had a history of inflammatory disease, CVD, diabetes mellitus, or chronic kidney disease. The local institutional ethics committee approved the protocol of the study, which was performed according to the Declaration of Helsinki. Also, written informed consent was obtained from all participants. Clinical examination and cardiovascular risk assessment A clinical examination of all patients with HS was carried out. The severity of HS was assessed by the HS Physician Global Assessment (PGA), which includes 6 stages (scale 0-5) with clear guidance for disease severity assessment (Table I).11 According to HS-PGA, HS was classified as moderate-severe-very severe when HS-PGA score was 3 or more. The Hurley grade of disease severity for each zone involved at the time of clinical examination was also evaluated.29 Disease severity was assessed by 2 dermatologists (M. A. G.-L. and M. L.-E.) in all the cases. Moreover, information on disease duration was also assessed in all patients. Patients and control subjects were interviewed about data of early cardiovascular events in firstdegree relatives and history of traditional CVD risk factors: hypertension (defined as a systolic blood pressure [BP] $140 mm Hg, diastolic BP $90 mm Hg, or the use of antihypertensive agents), hyperlipidemia (defined as total cholesterol and/or triglyceride levels in fasting plasma [200 mg/dL and/or [150 mg/dL, respectively, or prescription of lipidlowering medication), and history of smoking. Data on current and prior systemic therapy for HS were also registered. Body height and weight, body mass index (BMI), systolic BP, and diastolic BP were measured in all patients and control subjects at the time of the study.
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Laboratory assessment Venous blood samples were drawn after an overnight fast in all participants, and analyzed for total cholesterol, high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), triglycerides, glucose, high-sensitivity C-reactive protein, and erythrocyte sedimentation rate. Carotid ultrasonographic study Carotid ultrasound examination included the measurement of cIMT in the common carotid artery and the detection of focal plaques in the extracranial carotid tree. The study was performed using a commercially available scanner (Mylab 70 Esaote, Genoa, Italy) equipped with a 7 to 12 MHz linear transducer and the automated software-guided technique radiofrequencydQuality Intima Media Thickness in real-time (QIMT, Esaote, Maastricht, The Netherlands). Patients and control subjects were in a supine position during the examination and carotid arteries were scanned cross-sectionally and longitudinally. Carotid atherosclerotic plaque was identified as recommended in the Mannheim consensus: a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding cIMT value or demonstrates a thickness of greater than 1.5 mm as measured from the media-adventitia interface of the intima-lumen interface.30 Statistical analysis Results were reported as mean 6 SD, median and interquartile range, or proportions as appropriate. Quantitative variables were compared by the Student t test or Mann-Whitney U test as appropriate. Pearson x2 test or Fisher exact test were used to compare qualitative variables. Correlation analyses were performed separately in patients and control subjects using Pearson correlation coefficient or Spearman rho when appropriate. A backward stepwise multivariable linear regression analysis adjusted for age, sex, BP, serum LDL-c and HDL-c, current smoking, and BMI was performed to ascertain whether HS was associated with cIMT. In addition, an adjusted backward stepwise multivariable logistic regression analysis was performed to assess whether HS was related to carotid plaque measured by ultrasonography. A significance level of 5% was used. Software (STATA 12/SE, StataCorp, College Station, TX) was used in all the calculations.
RESULTS Demographic, clinical, and laboratory data A total of 68 patients with HS and 136 healthy control subjects were studied. The main demographic
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Table I. Hidradenitis suppurativa Physician Global Assessment Clear (score = 0) Minimal (score = 1) Mild (score = 2) Moderate (score = 3) Severe (score = 4) Very severe (score = 5)
No abscesses, no draining fistulae, no inflammatory nodules, and no noninflammatory nodules No abscesses, no draining fistulae, no inflammatory nodules, but presence of noninflammatory nodules No abscesses, no draining fistulae, and 1-4 inflammatory nodules, or 1 abscess or draining fistula and no inflammatory nodules No abscesses, no draining fistulae, $5 inflammatory nodules, and $1 inflammatory nodule, or 2-5 abscesses or draining fistula and \10 inflammatory nodules 2-5 Abscesses or draining fistula and [10 inflammatory nodules [5 Abscesses or draining fistula
Table II. Demographic, clinical, and laboratory findings of patients with hidradenitis suppurativa and healthy control subjects Variable
Age, y, mean 6 SD Men/women, n Disease duration at study onset, mean 6 SD HS-PGA score, 0-5 scale, n (%) Minimal, mild [\3] Moderate/severe/very severe [$3] Hurley stage, n (%) I II III History of classic cardiovascular risk factors, n (%) Current smokers Obesity Hyperlipidemia Hypertension Family history of early cardiovascular events, n (%) BMI, kg/m2, mean 6 SD Systolic BP, mm Hg, mean 6 SD Diastolic BP, mm Hg, mean 6 SD Total cholesterol, mg/dL, mean 6 SD LDL-c, mg/dL, mean 6 SD HDL-c, mg/dL, mean 6 SD Triglycerides, mg/dL, mean 6 SD Glucose, mg/dL, mean 6 SD ESR, mm/first h, median (IQR) hs-CRP, mg/L, median (IQR)
HS, n = 68
Control, n = 136
P
42.4 6 11.9 30/38 17.5 6 11.1
42.9 6 11.3 57/79 e
.72 .77
39 (57.4) 29 (42.6)
e e
e e
19 (28.0) 37 (54.4) 12 (17.6)
e e e
e e e
36 (26.5) 23 (17.2) 26 (19.1) 17 (12.5) 16 (11.9) 25.9 6 4.9 124.7 6 16.6 78.0 6 9.7 201.4 6 39.7 121.3 6 35.9 60.2 6 16.8 100.6 6 56.2 86.5 6 12.5 4.5 (2.0-8.0) 0.80 (0.50-2.00)
\.0001 \.0001 .33 .52 .82 \.0001 .006 .11 .004 .24 \.0001 .47 \.0001 \.0001 \.0001
43 (63.2) 28 (41.2) 9 (13.2) 11 (16.2) 9 (13.2) 29.0 6 5.2 131.5 6 16.2 80.3 6 9.2 185.1 6 33.0 115.2 6 32.2 50.5 6 16.1 95.4 6 44.9 94.3 6 12.3 13.0 (5.3-22.0) 3.40 (1.43-7.20)
BMI, Body mass index; BP, blood pressure; ESR, erythrocyte sedimentation rate; HDL-c, high-density lipoprotein cholesterol; HS, hidradenitis suppurativa; hs-CRP, high-sensitivity C-reactive protein; LDL-c, low-density lipoprotein cholesterol; PGA, Physician Global Assessment.
and clinical characteristics are summarized in Table II. The mean age did not significantly differ between the patients with HS and control subjects. The gender distribution for both groups was similar. According to the HS-PGA, 29 patients (42.6%) were classified as having minimal-mild HS (HS-PGA score \3) and the remaining 39 (57.4%) as having moderate-severe/very
severe HS (HS-PGA score $3). The mean duration of HS was 17.5 6 11.1 years (median 16.5 [interquartile range 8.3-25.0] years). There were no significant differences in the overall prevalence of hypertension and dyslipidemia between patients and control subjects. However, when compared with the control group, patients
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with HS were significantly more likely to be obese and smokers, and had higher BMI and systolic BP (Table II). Fasting plasma glucose levels, serum high-sensitivity C-reactive protein, and erythrocyte sedimentation rate were higher in patients than in control subjects, whereas serum HDL-c was significantly lower in patients with HS than in the control group (Table II). Carotid ultrasound findings Patients with HS had a significantly greater cIMT than control subjects (0.615 6 0.097 vs 0.578 6 0.098 mm; P = .012). In the linear regression multivariable analysis, after adjusting for age, sex, systolic BP, serum LDL-c and HDL-c levels, current smoking, and BMI, HS remained as a significant factor for higher cIMT (adjusted beta coefficient = 0.136; P = .011). The inclusion of additional variables to the regression model (serum glucose or triglyceride levels, diastolic BP) did not change this association. Carotid plaques were also more common in patients with HS (30.9%) than in control subjects (22.1%), but the difference was not statistically significant (P = .17). Nevertheless, we observed a significantly higher frequency of carotid plaques in the subgroup of patients with HS and moderatesevere/very severe disease (HS-PGA score $3; n = 39) when compared with control subjects (41% vs 22.1%; P = .023). In the logistic multivariable regression model adjusted for age, sex, systolic BP, serum LDL-c and HDL-c levels, current smoking, and BMI, HS was significantly related to the presence of carotid plaques (odds ratio 2.99, 95% confidence interval 1.26-7.13; P = .013). The inclusion of additional variables to the regression model (cIMT, serum glucose or triglyceride levels, diastolic BP) did not change this association. Correlation between cIMT and clinical variables in patients with HS A strong positive correlation was observed between the cIMT of patients with HS and age at the time of diagnosis (r = 0.615, P \ .0001) and disease duration (r = 0.453, P \ .0001). Significant correlation between cIMT and systolic BP (r = 0.331, P = .006) and fasting glucose levels (r = 0.331, P = .006) was also found (Table III). Differences between patients who have HS with and without plaques To further investigate the severity of the macrovascular atherosclerotic disease in patients with HS without clinically evident cardiovascular complications, we aimed to determine whether there were
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Table III. Correlation between carotid intimamedia thickness and clinical variables in patients with hidradenitis suppurativa cIMT Variable
Age, y Sex, female Disease duration, y HS-PGA score, $3 BMI, kg/m2 Current smoker, yes Systolic BP, mm Hg Diastolic BP, mm Hg Total cholesterol, mg/dL HDL-c, mg/dL LDL-c, mg/dL Triglycerides, mg/dL Fasting glucose, mg/dL hs-CRP, g/L ESR, mm/first h
r
0.6155 0.504 0.453 0.201 0.148 0.081 0.331 0.132 0.168 0.160 0.209 0.186 0.331 0.160 0.194
P
\.0001 \.0001 \.0001 .10 .22 .51 .006 .28 .17 .19 .08 .13 .006 .19 .11
BMI, Body mass index; BP, blood pressure; ESR, erythrocyte sedimentation rate; HDL-c, high-density lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; LDL-c, low-density lipoprotein cholesterol.
some clinical differences between patients who have HS with and without carotid plaques (Table IV). At the time of the study, the patients with plaques were older and had a significantly longer disease duration. They had more commonly severe forms of HS (HS-PGA score $3 and Hurley III stage) and were more frequently current smokers than patients with HS without carotid plaques. No statistical differences between patients who have HS with or without plaques according to sex, fasting glucose, HDL-c and LDL-c, or systolic BP and diastolic BP at the time of the study were observed. The cIMT values were significantly higher in patients with plaques than those without (0.653 6 0.107 vs 0.598 6 0.087 mm; P = .03) (Table IV).
DISCUSSION The results of this study show that patients with HS without clinically evident CVD have a higher prevalence of subclinical atherosclerosis by exhibiting a greater cIMT than control subjects matched for age and sex. Carotid plaques were also more frequently observed in patients with HS than in control subjects. However, this difference was only statistically significant between the subgroup of patients with moderate-severe/very severe HS (HS-PGA score $3) and the control group. In fact, we have found that the presence of carotid plaques are 3-fold more frequent in this subgroup of patients with HS compared with matched control subjects.
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Table IV. Main clinical and ultrasonographic differences between patients who have hidradenitis suppurativa with and without carotid plaques Variable
Age, y, mean 6 SD Men/women, n Age at disease onset, y Disease duration at time of study, y, mean 6 SD HS-PGA score moderate/severe/very severe [$3], n (%) Hurley stage, n (%) I II III BMI, kg/m2, mean 6 SD Normal \25 n (%) Overweight 25-29.9 n (%) Obese [30 n (%) Smoking status, n (%) Current Former Systolic BP, mm Hg, mean 6 SD Diastolic BP, mm Hg, mean 6 SD Total cholesterol, mg/dL, mean 6 SD HDL-c, mg/dL, mean 6 SD LDL-c, mg/dL, mean 6 SD Triglycerides, mg/dL, mean 6 SD Fasting glucose, mg/dL, mean 6 SD cIMT, mm, mean 6 SD
With plaques, n = 21
Without plaques, n = 47
P
49 6 9 8/13 25.3 6 12.9 23.4 6 9.8 16 (76.2)
38 6 12 22/25 24.3 6 9.8 14.9 6 10.8 23 (48.9)
.001 .60 .74 .003 .04
3 (14.3) 11 (52.4) 7 (33.3) 28.9 6 4.6 4 (19.0) 10 (47.6) 7 (33.4)
16 (34.0) 26 (55.3) 5 (10.7) 29.1 6 5.6 11 (23.4) 15 (31.9) 21 (44.7)
.07 .96 .03 .89 .76 .53 .38
17 (81) 4 (19.0) 135.3 6 17.5 81.1 6 9.4 191.2 6 34.2 50.6 6 17.9 120.1 6 35.6 98.7 6 38.2 95.4 6 13.9 0.653 6 0.107
26 (55.3) 14 (29.8) 129.8 6 9.4 8.0 6 9.3 182.5 6 32.6 50.6 6 15.4 112.7 6 30.7 93.9 6 47.9 93.8 6 11.7 0.598 6 0.087
.04 .55 .20 .67 .32 .99 .33 .69 .62 .03
BMI, Body mass index; BP, blood pressure; cIMT, carotid intima-media thickness; HDL-c, high-density lipoprotein cholesterol; HS, hidradenitis suppurativa; LDL-c, low-density lipoprotein cholesterol; PGA, Physician Global Assessment.
The formation of carotid plaques is considered a later step in the atherogenesis process and it is more strongly associated with an increased risk of CVD compared with increased cIMT.28,31 However, cIMT has also been shown to be independently associated with an increased risk for both coronary artery disease and stroke.28,31 The mechanism by which premature atherosclerosis develops in patients with HS remains to be clarified. A possible explanation would be that the higher prevalence of traditional CVD risk factors in patients with HS, such as increased smoking and obesity, could contribute to accelerated atherosclerosis. However, in our study the difference in cIMT between the patients with HS and control subjects remained significant after adjusting for these potential confounding risk factors. This suggests that HS itself, like other chronic inflammatory diseases, may be an independent risk factor for atherosclerosis, regardless of the presence of classic CVD risk factors. In this sense, the strong correlation between the disease duration of HS and cIMT detected in this study may suggest that a persistent chronic inflammation linked to HS may be of major importance to explain the accelerated atherogenesis.
These results are in agreement with various studies performed in patients with psoriasis that showed a correlation of abnormally increased cIMT with the duration of psoriasis.22,32,33 In keeping with that, our study also revealed a correlation of the disease with HS severity. In this regard, carotid plaques were more commonly observed in patients with HS who had longer disease duration and more severe forms of the disease. The mechanism of atherogenicity caused by inflammation is complex, although increasing evidence supports an important role for the inflammatory process in all phases of atherosclerosis.34 It is known that chronic and systemic inflammation may damage the vascular endothelium, and impaired endothelial function is an early step in the atherosclerosis process.21 In this regard, the inflammatory cells and the proinflammatory cytokines implicated in the chronic inflammation observed in HS may also promote the development of endothelial cell dysfunction and the subsequent development of accelerated atherogenesis. Our study has the inherent limitations of its cross-sectional design, mainly the inability to establish probable causality.
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