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Increased Suicide Risk in Patients with Hidradenitis Suppurativa
Accepted Manuscript Increased Suicide Risk in Patients with Hidradenitis Suppurativa Linnea Thorlacis, Arnon D. Cohen, Gunnar H. Gislason, Gregor B.E. Jemec, Alexander Egeberg PII:
S0022-202X(17)32955-X
DOI:
10.1016/j.jid.2017.09.008
Reference:
JID 1076
To appear in:
The Journal of Investigative Dermatology
Received Date: 5 June 2017 Revised Date:
30 August 2017
Accepted Date: 1 September 2017
Please cite this article as: Thorlacis L, Cohen AD, Gislason GH, Jemec GBE, Egeberg A, Increased Suicide Risk in Patients with Hidradenitis Suppurativa, The Journal of Investigative Dermatology (2017), doi: 10.1016/j.jid.2017.09.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Increased Suicide Risk in Patients with Hidradenitis Suppurativa Linnea Thorlacis1, Arnon D. Cohen2, 3, Gunnar H. Gislason4,5,6
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Gregor B.E. Jemec1, Alexander Egeberg7
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1) Department of Dermatology, Zealand University Hospital, Roskilde, University of Copenhagen, Denmark 2) Siaal Research Center for Family Medicine and Primary Care, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel 3) Chief Physician's Office, Department of Quality Measurements and Research, Clalit Health Services, Tel-Aviv, Israel 4) Department of Cardiology, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark 5) The Danish Heart Foundation, Copenhagen, Denmark 6) The National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark 7) Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
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Correspondence: Alexander Egeberg, Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark E-mail: [email protected]
Work was done in Roskilde and Copenhagen, Denmark
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Short title: Hidradenitis and psychiatric comorbidity
Abbreviations: HS, Hidradenitis Suppurativa; OR, Odds Ratio; CI, Confidence Interval; HR, Hazard Ratio; PY, Person-Years Page 1 of 20
ACCEPTED MANUSCRIPT ABSTRACT
Patients with skin disorders are considered at a higher risk of depression and anxiety than the background population. Patients with hidradenitis suppurativa (HS) may be particularly affected.
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We explored the association between HS and depression, anxiety, and completed suicides in the Danish national registries expanding to include data on suicidal behavior, using both a crosssectional and a cohort study design. Both designs included 7,732 patients with HS and a
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background population of 4,354,137. The cohort study revealed that HS-patients had an increased risk of completed suicide after adjustment for confounding factors (11/7,732 vs. 2,904/4,354,137)
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(Hazard Ratio (HR) 2.42 (1.07-5.45); P=0.0334) and an increased risk of antidepressant drug use (HR 1.30 (1.17-1.45); P<0.0001). In contrast to previous studies the cross-sectional baseline data revealed non-significant association with depression (Odds Ratio (OR) 1.13 (0.87-1.47); P=0.36 and hospitalization due to depression (OR 1.32 (0.94-1.85); P=0.1083). To the best of our
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knowledge, this is the first study to report on the increased risk of completed suicide among HS patients. The increased risk of completed suicide is not solely explained by lifestyle and demographic differences and the results highlight the profound impact HS has on the lives of
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patients with this often devastating disease.
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ACCEPTED MANUSCRIPT INTRODUCTION Hidradenitis Suppurativa (HS) is a chronic, inflammatory skin disease. The estimated prevalence of HS is 0.1-4 % worldwide (Garg et al., 2017, Jemec et al., 1996, Revuz et al., 2008, Vinding et al.,
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2014). The primary lesions are inflammatory nodules that may develop into abscesses and sinus tracts with subsequent scarring, affecting flexural sites such as the axillae and groins on a recurrent basis (Jemec, 2012, Zouboulis et al., 2015). Lesions of HS are typically described by patients as
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painful boils which, along with associated pus and odor, are associated with significant stigma, which negatively influences the health related quality of life (HRQoL) of patients through a range
Riis et al., 2016, Tugnoli et al., 2016).
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of psychosocial mechanisms (Deckers and Kimball, 2016, Kouris et al., 2016, Matusiak et al., 2010,
The disease has several, clinically significant co-morbidities in addition to the pain and suppuration (Ring et al., 2016, Shlyankevich et al., 2014, Vazquez et al., 2013) and although dermatology
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patients generally have an increased risk of phychiatric disease (Dalgard et al., 2015), there are indications that HS patients may be particularly affected. A review on the handicap of HS (Deckers and Kimball, 2016) identified three studies that used questionnaires to determine the prevalence of
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depression in HS (Kurek et al., 2013, Matusiak et al., 2010, Onderdijk et al., 2013) and one study that investigated the prevalence of depression in HS using the large Clalit database containing
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aggregate heath data on 4.4 million inhabitants of Israel (Shavit et al., 2015). The three questionnaire studies (Kurek et al., 2013, Matusiak et al., 2010, Onderdijk et al., 2013) found a prevalence of depression between 9% and 39% in patients with HS, but unfortunately used three different questionnaires, making direct comparison impossible (Deckers and Kimball, 2016). Shavit et al. found 5.9% of the 3207 included patients with HS to have a co-morbid diagnosis of depression with a significantly increased Odds Ratio (OR) (95% Confidence Interval (CI)) of 1.7 (1.4–2.1) for depression as a comorbidity to HS after adjusting for age and gender (Shavit et al.,
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ACCEPTED MANUSCRIPT 2015). In addition to these studies, Vazques et al. reviewed data form the Olmstead County Population study and found 42.9% of the 268 included HS patients to have a co-morbid diagnosis of depression (Vazquez et al., 2013), Vangipuram et al. found a concurrent diagnosis of depression in
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24.4% of 283 included HS patients (Vangipuram et al., 2016), Scheinfeld et al. found a questionnaire based diagnosis of depression in 41.8% of the 154 included HS patients (Scheinfeld et al., 2016) and a smaller Finish study found a questionnaire based diagnosis of depression in 38.5%
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of 26 included HS patients (Kluger et al., 2017). In summary, all previus studies on depression in HS have found that HS patients have an augmented risk of depression, but the prevalence of
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depression in HS has been subject to considerable between-study variations, depending on the applied methodology.
Only a few studies have investigated the association between HS and anxiety. The Clalit database study found a co-morbid diagnosis of anxiety in 3.9% of the 3207 included HS
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patients with a significantly increased OR (95% CI) of 1.7 (1.3–2.1) (Shavit et al., 2015) and a casecontrol study involving 94 HS patients and 94 healthy control found that HS patients presented with higher questionnaire based diagnosis of anxiety (6.41 ± 3.31 vs. 5.00 ± 1.59, p < 0.001) than the
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healthy controls (Kouris et al., 2016).
No studies on the association between HS and complete suicide appears when you
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search the literature.
The current study aims to explore depression, anxiety and completed suicides in HS
patients further using Danish national registries, expanding the analysis to include prescription patterns of antidepressants and anxiolytic drugs.
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RESULTS The study included 7,732 diagnosed HS patients with a mean age (Standard Deviation, SD) of 45.8
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(12.2) years and a background population of 4,354,137 with a mean age (SD) of 48.7 (18.0) years. At baseline, smoking, alcohol abuse and diabetes was more prevalent among HS patients compared with the general population, as was the prevalence of depression, anxiety, antidepressant- and
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anxiolytic drug use, respectively (Table 1).
Table 2 shows ORs for association between HS and psychiatric comorbidity at
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baseline adjusted for age, sex, socioeconomic status, smoking, alcohol abuse, and healthcare services use with increased ORs (95% CI) for anxiety (1.73 (1.23-2.41); P=0.0014), hospitalization due to anxiety (2.06 (1.25-3.40); P=0.0049), antidepressant drug use (1.46 (1.36-1.58); P<0.0001) and anxiolytic drug use (1.37 (1.27-1.48); P<0.0001) within the preceding five years. ORs for
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diagnosed depression (1.13 (0.87-1.47); P=0.3647) and hospitalization due to depression (1.32 (0.94-1.85); P=0.1083) were not increased.
We found an incidence rate (per 1,000 person-years [PY]) (95% CI) for depression of
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0.68 (0.46-1.00) for HS patients compared with 0.35 (0.35-0.36) in the background population (Table 3). Eleven events of completed suicide were observed in the HS patient population with an
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incidence rate of 0.29/1,000 PY (95% CI 0.16-0.53). The corresponding number of completed suicides in the background population was 2,904 with an incidence rate of 0.14/1,000 PY (95% CI 0.13-0.14) (Table 3).
Our fully adjusted analysis showed no increased risk (presented as hazard ratios, HR
with 95% CI) of first-time depression (1.12 (0.58-2.17); P=0.7289), hospitalization due to depression (1.61 (0.66-3.90); P=0.2947), risk of first-time anxiety (1.42 (0.73-2.74); P=0.3033), hospitalization due to anxiety (2.04 (0.84-5.00); P=0.1170) or anxiolytic drug use (1.05 (0.90-1.23);
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ACCEPTED MANUSCRIPT P=0.5455) (Table 4). The risk of completed suicide (2.42 (1.07-5.45); P=0.0334) and antidepressant drug use (1.30 (1.17-1.45); P<0.0001) were increased.
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DISCUSSION Our most predominant finding was the significantly increased risk of completed suicide in the cohort of HS patients, which remained increased even after adjustment for confounding factors. The
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increased risk may not solely be explained by demographic and lifestyle factors and the result may be seen as as a very clear indicator of how profoundly HS can affect the patients` lives. Reports on
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completed suicide among dermatological patients are far fewer than reports on suicidal ideation or depression, and in general, limited data have been published on the risk of self-harm, suicide attempts and completed suicide in patients with other common inflammatory skin diseases such as psoriasis, acne and atopic dermatitis. A recent systematic review (Chi et al., 2017) which included
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five population-based cohort studies of considered high quality (Egeberg et al., 2016b, Kimball et al., 2012, Kurd et al., 2010, Singhal et al., 2014, Wu et al., 2017) found no increase in the risk of completed suicide (risk ratio [RR] 1.13; 95% CI 0.87–1.46), suicide attempt (RR 1.25; 95% CI
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0.89–1.75), or suicidality (RR 1.26; 95% CI 0.97–1.64) among people with psoriasis. Several studies have reported a high prevalence of suicidal ideation in patients with acne, but a review on
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suicide risk in skin disorders (Picardi et al., 2013) only reported on one study investigating the risk of completed suicide in patients with severe acne (Sundstrom et al., 2010). Although the risk of completed suicide estimates were higher for patients with acne as compared with the general population in this study, the findings were nonsignificant. Similarly, an increased risk of suicidal ideation was reported in patients with atopic dermatitis (Dieris-Hirche J, 2009, Kimata, 2006, Zachariae et al., 2004), whereas the risk of completed suicide is not increased in patients with atopic dermatitis compared with the general population (Thyssen et al., 2017). These observations strongly
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ACCEPTED MANUSCRIPT suggest that our finding of increased risk of completed suicide is unique, and the results underlines the strong psychological effect of HS. In accordance with previous studies we found a higher prevalence of depression and anxiety in HS
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patients compared with the background population in our cross-sectional analysis at baseline. Adjusted ORs for association between HS and psychiatric comorbidity at baseline showed
significantly increased association with anxiety, hospitalization due to anxiety, antidepressant and
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anxiolytic drug use but no increased ORs for depression and hospitalization due to depression. Shavit et al. did find a significantly increased OR of association between depression and HS, albeit
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that the estimates were only adjusted for age and gender (Shavit et al., 2015). Using a similar approach to that of Shavit et al., we also found ORs for depression and hospitalization due to depression at baseline significantly increased. The loss of significance association in the fully adjusted analysis suggests that this increased risk can be explained by socioeconomic and lifestyle
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disparities among the two groups and may therefore be taken to reflect the socioeconomic associations of HS (Deckers et al., 2016, Theut Riis et al., 2017). However, causality cannot be inferred from cross-sectional studies and while the socioeconomic status can be an aggravating
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factor for depression, HS could also be the reason for the lower socioeconomic status. If this is the case, the socioeconomic status adjusted results might be too restrictive and the `true´rates will be
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closer to age and gender only adjusted results. In addition, our cohort study design did find a significantly increased risk of antidepressant drug use, even in fully adjusted estimates, albeit that the risk of first-time diagnosed depression or hospitalization due to depression was not significantly increased. One possible explanation for this could be that antidepressant drugs may be prescribed for milder cases of depression in the primary sector without the patient receiving a formal depression diagnosis. The significantly increased risk of antidepressant drug use is therefore a
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ACCEPTED MANUSCRIPT conceivable indication that HS patients have an increased risk of mild or moderate depression that may not require hospital treatment. Our cross-sectional analysis at baseline found an increased risk of anxiety,
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hospitalization due to anxiety and anxiolytic drug use, whereas our cohort-study did not. It may be speculated, that since HS is a chronic or recurrent disease with a significant diagnostic delay (Saunte et al., 2015), most patients who reach hospital care have a long history of HS and selection
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bias may therefore occur. Anxiety may be hypothesized to be an early phenomenon meaning that it has developed before the entry of patients into the cohort. Conversely, attrition may play a role
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since prevalent cases were excluded in the cohort study. Quality of care may also influence these results. The knowledge about the management of HS patients is rapidly increasing and was much less developed before 2008 and the lack of association in the cohort study may therefore reflect better standards of care.
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Our study revealed both an increased risk of completed suicide and indicated an increased risk of depression and anxiety among patients with HS. However, no conclusion about causality and link between these diagnoses can be made based on our results, and it should be noted
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that suicide is a symptom of a multitude of (psychiatric) diseases, not just depression and anxiety. Several important limitations apply to the interpretation of our results. Due to the
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observational design of our study, we cannot determine causality. Selection bias towards moderatesevere cases with an associated higher level of co-morbidities may play a role because of the hospital setting of selection of HS patient to the study. Misclassification may also play a role as the inclusion is based on correct ICD coding of cases.(Ingvarsson, 2017, Strunk et al., 2017) It is also a limitation that the Danish population is homogenous and predominantly white, and extrapolation of results to patients of other ethnicities should be conducted with caution.
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ACCEPTED MANUSCRIPT On the other hand, the study also has several important strengths. These include the high accuracy of the nationwide registries as well as the available information on household income, which minimized bias associated with sex, age, socioeconomic status, smoking, alcohol
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abuse and healthcare consumption. In addition, the design that combined a cross-sectional study with a cohort study providing follow-up data and the large included number in the analyses add credibility to our findings.
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In summary, we have found a significantly increased risk of completed suicide in HS patients independent of measured confounders. We have also found an increased risk of depression
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and anxiety among HS patients compared with the background population, but our further analysis indicated that this increased risk by large is explained by confounding factors. This does however not make the psychiatric comorbidities less important, and all in all the results emphasizes the inescapable importance of clinicians treating the HS patient with psychiatric comorbidities in mind.
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Ideally, this includes a structured development of strategies to prevent or minimize psychological comorbidities as well as the implementation of specific routines for clinical management. Effective assessment and treatment of psychiatric comorbidities and suicidality in HS patients with skin
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diseases depends on a multidisciplinary approach with access to a psychiatrist if needed. The use of patient reported outcomes including questionnaires for depression, anxiety and suicidal ideation in
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order to detect early stages and intervene to lower risk of progression is also recommended.
MATERIAL AND METHODS This study is one of a series of explorative epidemiological studies of HS all using a similar approach. Please see (Egeberg et al., 2016a, Egeberg et al., 2017, Theut Riis et al., 2016).
Data sources
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ACCEPTED MANUSCRIPT Ethics committee approval is not required for registry studies in Denmark, in agreement with legal requirements the study was however approved by the Danish Data Protection Agency (ref. 2007-580015, int. ref. GEH-2014-018, I-Suite 02736). The study was conducted in accordance with the
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Strengthening the Reporting of Observational Studies in Epidemiology recommendations (von Elm et al., 2007). In Denmark, the universal health care system provides the opportunities to perform population-based cohort studies. In brief, all residents are assigned a unique and permanent civil
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registration number at birth or on immigration. This unique identifier allows unambiguous linkage among all population-based administrative and health registries in the country (Schmidt et al.,
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2014). Tax-supported health care that ensures that all citizens have unrestricted access to hospitals and general practitioners. Information pertaining all patients admitted to or seen on an outpatient basis in Danish hospitals, and in some private clinics, is stored in the Danish National Patient Register, and coded in accordance with the International Classification of Diseases (ICD)( Danish
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version) (Andersen et al., 1999). In addition, all prescriptions are recorded in the Register of Medicinal Product Statistics, and classified according to the Anatomical Therapeutic Chemical (ATC) Classification System (Gaist et al., 1997). All deaths and causes of deaths are obtained from
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Larsen, 2011).
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electronic death certificates and registered in the National Causes of Death Registry (Helweg-
Study population
The study population consisted of all Danish adults (≥18 years) alive and resident in Denmark on January 1st 2008 (i.e. date of study start for all individuals in the cohort). Subjects were followed until December 31st 2012, migration, death, or the occurrence of an endpoint, whichever occurred first. All patients with a recorded diagnosis of HS (ICD-8 705.91 and ICD-10 L73.2) in the Danish National Patient Register prior to study start were classified as having HS. Tax-reported household
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ACCEPTED MANUSCRIPT income information was obtained from Statistics Denmark. The collection of the comorbidity data described in Table 1 is described elsewhere (Egeberg et al., 2016a, Egeberg et al., 2016c, Olesen et
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al., 2011).
Outcomes
The endpoints were a primary diagnosis in the Danish National Patient Register of depression (ICD-
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8 296.09, 296.29, 296.99, 298.09, 300.19, 300.49 and ICD-10 F32-33), anxiety (ICD-8 300.0, 300.2 and ICD-10 F40-41), hospitalization for depression or anxiety, a recorded completed suicide in the
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National Causes of Death Registry (ICD-10 X60–X84), respectively, as well as a claimed prescription for antidepressants (ATC N06A), or anxiolytic drugs (ATC N05B), respectively.
Statistical analysis
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Summary statistics were presented as means with standard deviation (SD) for normally distributed variables, medians and interquartile range (IQR) for non-normally distributed continuous variables and frequencies for categorical variables. The baseline period prevalence was determined as the
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percentage of individuals with one of the pre-specified diagnoses, or claimed a prescription, as appropriate, within the past five years before study start. A cross-sectional design was applied on
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January 1st 2008 using logistic regression models to assess the odds ratios (ORs) of a history of psychiatric morbidity within the past five years. Moreover, we performed a cohort study in which the entire cohort was followed from study start and until the first of either December 31st 2012, death, migration, or the occurrence of an endpoint. SAS statistical software version 9.4 (SAS Institute Inc. Cary, NC, USA) and STATA software version 13.0 (StataCorp, College Station, TX, USA) were used to summarize incidence rates per 1,000 person-years, and Cox regression models were performed to obtain HRs in the cohort study. For the cohort study, incidence was examined for
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ACCEPTED MANUSCRIPT all individuals without a history of the condition prior to study start, i.e. analyses of first-time outcome. ORs and HRs were calculated as age- and sex-adjusted, and fully adjusted (in which age, sex, socioeconomic status, smoking, alcohol abuse, and healthcare consumption were considered).
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Socioeconomic status was calculated based on the mean annual income during the 5-year period before study start, and standardized by age. Model assumptions including the proportional hazards assumption was tested and found to be valid. All statistical tests were conducted using a level of
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significance of 0.05, and results were reported with 95% CIs, where applicable.
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CONFLICT OF INTEREST
Dr. Jemec is a consultant and investigator for AbbVie and Novartis, has received unrestricted grants from Leo Pharma, and sits on the Advisory Board of AbbVie, InflaRx, Novartis, Janssen Pharmaceuticals, MSD and Pierre Fabre; and investigator for Abbvie, Novartis, Sanofi and
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Regeneron. Dr. Gislason is supported by an unrestricted research scholarship from the Novo Nordisk Foundation. Dr. Cohen has recived research grants from Novartis and has served as a consultant, advisor or speaker to Abbvie, Dexcel pharma, Janssen, Novartis, Perrigo, Pfizer and
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Rafa. Dr. Egeberg has received research funding from Pfizer and Eli Lilly, and honoraria as
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consultant and/or speaker from Pfizer, Eli Lilly, Novartis, Galderma, and Janssen Pharmaceuticals.
ACKNOWLEDSEMENTS
Author Contributions Drs. Egeberg and Gislason had full access to all of 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: Egeberg and Jemec. Acquisition, analysis, and interpretation of data: All authors. Drafting of the
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ACCEPTED MANUSCRIPT manuscript: Egeberg, Jemec, and Thorlacius. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Egeberg and Gislason. Obtained funding: None. Administrative, technical, or material support: All authors. Study supervision: Egeberg and
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Jemec.
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Scheinfeld N, Sundaram M, Teixeira H, Gu Y, Okun M. Reduction in pain scores and improvement in depressive symptoms in patients with hidradenitis suppurativa treated with adalimumab in a phase 2, randomized, placebo-controlled trial. Dermatology online journal 2016;22(3). Schmidt M, Pedersen L, Sorensen HT. The Danish Civil Registration System as a tool in epidemiology. European journal of epidemiology 2014;29(8):541-9. Shavit E, Dreiher J, Freud T, Halevy S, Vinker S, Cohen AD. Psychiatric comorbidities in 3207 patients with hidradenitis suppurativa. Journal of the European Academy of Dermatology and Venereology : JEADV 2015;29(2):371-6. Shlyankevich J, Chen AJ, Kim GE, Kimball AB. Hidradenitis suppurativa is a systemic disease with substantial comorbidity burden: a chart-verified case-control analysis. Journal of the American Academy of Dermatology 2014;71(6):1144-50. Singhal A, Ross J, Seminog O, Hawton K, Goldacre MJ. Risk of self-harm and suicide in people with specific psychiatric and physical disorders: comparisons between disorders using English national record linkage. Journal of the Royal Society of Medicine 2014;107(5):194204. Strunk A, Midura M, Papagermanos V, Alloo A, Garg A. Validation of a Case-Finding Algorithm for Hidradenitis Suppurativa Using Administrative Coding from a Clinical Database. Dermatology (Basel, Switzerland) 2017. Sundstrom A, Alfredsson L, Sjolin-Forsberg G, Gerden B, Bergman U, Jokinen J. Association of suicide attempts with acne and treatment with isotretinoin: retrospective Swedish cohort study. BMJ (Clinical research ed) 2010;341:c5812. Theut Riis P, Egeberg A, Gislason GH, Jemec GB. Patients with hidradenitis suppurativa have no increased risk of Alzheimer disease. The British journal of dermatology 2016. Theut Riis P, Thorlacius L, Knudsen List E, Jemec GBE. A pilot study of unemployment in patients with hidradenitis suppurativa in Denmark. The British journal of dermatology 2017;176(4):1083-5. Thyssen JP, Hamann CR, Linneberg A, Dantoft TM, Skov L, Gislason GH, et al. Atopic dermatitis is associated with anxiety, depression, and suicidal ideation, but not with psychiatric hospitalization or suicide. Allergy 2017. Tugnoli S, Bettoli V, Agnoli C, Caracciolo S. [Emotions and bodily experience in Hidradenitis Suppurative-Acne Inversa]. La Clinica terapeutica 2016;167(3):e55-62. Vangipuram R, Vaidya T, Jandarov R, Alikhan A. Factors Contributing to Depression and Chronic Pain in Patients with Hidradenitis Suppurativa: Results from a Single-Center Retrospective Review. Dermatology (Basel, Switzerland) 2016;232(6):692-5. 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. The Journal of investigative dermatology 2013;133(1):97-103. Vinding GR, Miller IM, Zarchi K, Ibler KS, Ellervik C, Jemec GB. The prevalence of inverse recurrent suppuration: a population-based study of possible hidradenitis suppurativa. The British journal of dermatology 2014;170(4):884-9. von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet (London, England) 2007;370(9596):1453-7. Wu JJ, Penfold RB, Primatesta P, Fox TK, Stewart C, Reddy SP, et al. The risk of depression, suicidal ideation and suicide attempt in patients with psoriasis, psoriatic arthritis or ankylosing spondylitis. Journal of the European Academy of Dermatology and Venereology : JEADV 2017;31(7):1168-75.
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Zachariae R, Zachariae C, Ibsen HH, Mortensen JT, Wulf HC. Psychological symptoms and quality of life of dermatology outpatients and hospitalized dermatology patients. Acta dermatovenereologica 2004;84(3):205-12. Zouboulis CC, Del Marmol V, Mrowietz U, Prens EP, Tzellos T, Jemec GB. Hidradenitis Suppurativa/Acne Inversa: Criteria for Diagnosis, Severity Assessment, Classification and Disease Evaluation. Dermatology (Basel, Switzerland) 2015;231(2):184-90.
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TABLES
48.7 (18.0) NA
45.8 (12.2) 9.6 (4.6-16.1)
2,210,356 (50.8) 2,143,781 (49.2)
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Prevalence at baseline*, n (%) Depression Hospitalization due to depression Anxiety Hospitalization due to anxiety Antidepressant drug use Anxiolytic drug use
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Hidradenitis suppurativa (n=7,732)
5,687 (73.6) 2,045 (26.4)
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Smoking, n (%) Alcohol abuse, n (%) Diabetes, n (%) Hypertension, n (%)
General population (n=4,354,137)
871,896 (20.0) 870,665 (20.0) 870,209 (20.0) 870,440 (20.0) 870,927 (20.0)
621 (8.3) 1,673 (21.6) 2,127 (27.5) 1,901 (24.6) 1,410 (18.2)
430,882 (9.9) 60,801 (1.4) 157,662 (3.6) 527,777 (12.1)
2,055 (26.6) 201 (2.6) 532 (6.9) 942 (12.2)
35,031 (0.8) 18,783 (0.4) 13,873 (0.3) 5,651 (0.1) 787,399 (18.1) 782,482 (18.0)
126 (1.6) 72 (0.9) 64 (0.8) 28 (0.4) 2,563 (33.2) 2,297 (29.7)
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Age, mean (SD) Disease duration, median (IQR) Sex, n (%) Women Men Socioeconomic status, n (%) Lowest Below average Average Above average Highest
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Table 1 – Baseline characteristics of the study population
IQR, interquartile range; NA, not applicable; SD, standard deviation *Disease activity within past 5 years
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ACCEPTED MANUSCRIPT Table 2 –Association between hidradenitis suppurativa and psychiatric comorbidity at baseline (cross-sectional study design)
1.13
0.87-1.47
0.3647
1.32
0.94-1.85
0.1083
1.73
1.23-2.41
0.0014
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1.90
1.59-2.26 <0.0001
Hospitalization due to depression
2.06
1.63-2.60 <0.0001
Anxiety
2.34
1.83-3.00 <0.0001
Hospitalization due to anxiety
2.65
1.83-3.85 <0.0001
2.06
1.25-3.40
0.0049
Antidepressant drug use
2.19
2.09-2.30 <0.0001
1.46
1.36-1.58 <0.0001
Anxiolytic drug use
2.02
1.92-2.13 <0.0001
1.37
1.27-1.48 <0.0001
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Depression
Fully adjusted* Odds ratio 95% CI p-value
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Age- and sex adjusted Odds ratio 95% CI p-value
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CI, confidence interval *Adjusted for age, sex, socioeconomic status, smoking, alcohol abuse, and healthcare consumption
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ACCEPTED MANUSCRIPT Table 3 – Summary of number of new events, follow-up time, and incidence rates of the study outcomes per 1,000 person-years General population Hidradenitis suppurativa Depression Follow-up time, years Number of events Incidence rate/1,000 PY (95% CI)
20,707,731 7,317 0.35 (0.35-0.36)
Hospitalization due to depression Follow-up time, years Number of events Incidence rate/1,000 PY (95% CI)
20,792,968 2,696 0.13 (0.12-0.13)
Anxiety Follow-up time, years Number of events Incidence rate/1,000 PY (95% CI)
20,806,412 4,572 0.22 (0.21-0.23)
37,249 15 0.40 (0.24-0.67)
20,853,061 1,707 0.08 (0.08-0.09)
37,451 9 0.24 (0.13-0.46)
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Hospitalization due to anxiety Follow-up time, years Number of events Incidence rate/1,000 PY (95% CI)
36,940 25 0.68 (0.46-1.00)
20,882,557 2,904 0.14 (0.13-0.14)
37,611 11 0.29 (0.16-0.53)
Antidepressant drug use Follow-up time, years Number of events Incidence rate/1,000 PY (95% CI)
16,465,559 313,029 19.01 (18.94-19.08)
23,186 802 34.59 (32.28-37.07)
16,933,337 149,563 8.83 (8.79-8.88)
25,854 336 13.00 (11.68-14.46)
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Suicide Follow-up time, years Number of events Incidence rate/1,000 PY (95% CI)
Anxiolytic drug use Follow-up time, years Number of events Incidence rate/1,000 PY (95% CI)
CI, confidence interval; PY, person-years
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ACCEPTED MANUSCRIPT Table 4 – Hazard ratios for risk of first-time depression, anxiety, antidepressant or anxiolytic drug use, and completed suicide, respectively, among patients with hidradenitis suppurativa compared with the general population (cohort study design) Fully adjusted* Hazard ratio 95% CI p-value
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Age- and sex adjusted Hazard ratio 95% CI p-value 2.08
1.40-3.08 0.0003
1.12
0.58-2.17 0.7289
Hospitalization due to depression
2.18
1.13-4.19 0.0200
1.61
0.66-3.90 0.2947
Anxiety
1.63
0.98-2.70 0.0595
1.42
0.73-2.74 0.3033
Hospitalization due to anxiety
2.74
1.42-5.28 0.0026
2.04
0.84-5.00 0.1170
Completed suicide
2.89
1.60-5.23 0.0004
2.42
1.07-5.45 0.0334
Antidepressant drug use
1.74
1.62-1.86 <0.0001
1.30
1.17-1.45 <0.0001
Anxiolytic drug use
1.54
1.38-1.71 <0.0001
1.05
0.90-1.23 0.5455
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Depression
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CI, confidence interval *Adjusted for age, sex, socioeconomic status, smoking, alcohol abuse, and healthcare consumption
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S0022-202X(17)32955-X
DOI:
10.1016/j.jid.2017.09.008
Reference:
JID 1076
To appear in:
The Journal of Investigative Dermatology
Received Date: 5 June 2017 Revised Date:
30 August 2017
Accepted Date: 1 September 2017
Please cite this article as: Thorlacis L, Cohen AD, Gislason GH, Jemec GBE, Egeberg A, Increased Suicide Risk in Patients with Hidradenitis Suppurativa, The Journal of Investigative Dermatology (2017), doi: 10.1016/j.jid.2017.09.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Increased Suicide Risk in Patients with Hidradenitis Suppurativa Linnea Thorlacis1, Arnon D. Cohen2, 3, Gunnar H. Gislason4,5,6
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Gregor B.E. Jemec1, Alexander Egeberg7
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1) Department of Dermatology, Zealand University Hospital, Roskilde, University of Copenhagen, Denmark 2) Siaal Research Center for Family Medicine and Primary Care, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel 3) Chief Physician's Office, Department of Quality Measurements and Research, Clalit Health Services, Tel-Aviv, Israel 4) Department of Cardiology, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark 5) The Danish Heart Foundation, Copenhagen, Denmark 6) The National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark 7) Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
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Correspondence: Alexander Egeberg, Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark E-mail: [email protected]
Work was done in Roskilde and Copenhagen, Denmark
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Short title: Hidradenitis and psychiatric comorbidity
Abbreviations: HS, Hidradenitis Suppurativa; OR, Odds Ratio; CI, Confidence Interval; HR, Hazard Ratio; PY, Person-Years Page 1 of 20
ACCEPTED MANUSCRIPT ABSTRACT
Patients with skin disorders are considered at a higher risk of depression and anxiety than the background population. Patients with hidradenitis suppurativa (HS) may be particularly affected.
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We explored the association between HS and depression, anxiety, and completed suicides in the Danish national registries expanding to include data on suicidal behavior, using both a crosssectional and a cohort study design. Both designs included 7,732 patients with HS and a
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background population of 4,354,137. The cohort study revealed that HS-patients had an increased risk of completed suicide after adjustment for confounding factors (11/7,732 vs. 2,904/4,354,137)
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(Hazard Ratio (HR) 2.42 (1.07-5.45); P=0.0334) and an increased risk of antidepressant drug use (HR 1.30 (1.17-1.45); P<0.0001). In contrast to previous studies the cross-sectional baseline data revealed non-significant association with depression (Odds Ratio (OR) 1.13 (0.87-1.47); P=0.36 and hospitalization due to depression (OR 1.32 (0.94-1.85); P=0.1083). To the best of our
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knowledge, this is the first study to report on the increased risk of completed suicide among HS patients. The increased risk of completed suicide is not solely explained by lifestyle and demographic differences and the results highlight the profound impact HS has on the lives of
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patients with this often devastating disease.
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ACCEPTED MANUSCRIPT INTRODUCTION Hidradenitis Suppurativa (HS) is a chronic, inflammatory skin disease. The estimated prevalence of HS is 0.1-4 % worldwide (Garg et al., 2017, Jemec et al., 1996, Revuz et al., 2008, Vinding et al.,
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2014). The primary lesions are inflammatory nodules that may develop into abscesses and sinus tracts with subsequent scarring, affecting flexural sites such as the axillae and groins on a recurrent basis (Jemec, 2012, Zouboulis et al., 2015). Lesions of HS are typically described by patients as
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painful boils which, along with associated pus and odor, are associated with significant stigma, which negatively influences the health related quality of life (HRQoL) of patients through a range
Riis et al., 2016, Tugnoli et al., 2016).
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of psychosocial mechanisms (Deckers and Kimball, 2016, Kouris et al., 2016, Matusiak et al., 2010,
The disease has several, clinically significant co-morbidities in addition to the pain and suppuration (Ring et al., 2016, Shlyankevich et al., 2014, Vazquez et al., 2013) and although dermatology
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patients generally have an increased risk of phychiatric disease (Dalgard et al., 2015), there are indications that HS patients may be particularly affected. A review on the handicap of HS (Deckers and Kimball, 2016) identified three studies that used questionnaires to determine the prevalence of
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depression in HS (Kurek et al., 2013, Matusiak et al., 2010, Onderdijk et al., 2013) and one study that investigated the prevalence of depression in HS using the large Clalit database containing
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aggregate heath data on 4.4 million inhabitants of Israel (Shavit et al., 2015). The three questionnaire studies (Kurek et al., 2013, Matusiak et al., 2010, Onderdijk et al., 2013) found a prevalence of depression between 9% and 39% in patients with HS, but unfortunately used three different questionnaires, making direct comparison impossible (Deckers and Kimball, 2016). Shavit et al. found 5.9% of the 3207 included patients with HS to have a co-morbid diagnosis of depression with a significantly increased Odds Ratio (OR) (95% Confidence Interval (CI)) of 1.7 (1.4–2.1) for depression as a comorbidity to HS after adjusting for age and gender (Shavit et al.,
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ACCEPTED MANUSCRIPT 2015). In addition to these studies, Vazques et al. reviewed data form the Olmstead County Population study and found 42.9% of the 268 included HS patients to have a co-morbid diagnosis of depression (Vazquez et al., 2013), Vangipuram et al. found a concurrent diagnosis of depression in
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24.4% of 283 included HS patients (Vangipuram et al., 2016), Scheinfeld et al. found a questionnaire based diagnosis of depression in 41.8% of the 154 included HS patients (Scheinfeld et al., 2016) and a smaller Finish study found a questionnaire based diagnosis of depression in 38.5%
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of 26 included HS patients (Kluger et al., 2017). In summary, all previus studies on depression in HS have found that HS patients have an augmented risk of depression, but the prevalence of
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depression in HS has been subject to considerable between-study variations, depending on the applied methodology.
Only a few studies have investigated the association between HS and anxiety. The Clalit database study found a co-morbid diagnosis of anxiety in 3.9% of the 3207 included HS
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patients with a significantly increased OR (95% CI) of 1.7 (1.3–2.1) (Shavit et al., 2015) and a casecontrol study involving 94 HS patients and 94 healthy control found that HS patients presented with higher questionnaire based diagnosis of anxiety (6.41 ± 3.31 vs. 5.00 ± 1.59, p < 0.001) than the
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healthy controls (Kouris et al., 2016).
No studies on the association between HS and complete suicide appears when you
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search the literature.
The current study aims to explore depression, anxiety and completed suicides in HS
patients further using Danish national registries, expanding the analysis to include prescription patterns of antidepressants and anxiolytic drugs.
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RESULTS The study included 7,732 diagnosed HS patients with a mean age (Standard Deviation, SD) of 45.8
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(12.2) years and a background population of 4,354,137 with a mean age (SD) of 48.7 (18.0) years. At baseline, smoking, alcohol abuse and diabetes was more prevalent among HS patients compared with the general population, as was the prevalence of depression, anxiety, antidepressant- and
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anxiolytic drug use, respectively (Table 1).
Table 2 shows ORs for association between HS and psychiatric comorbidity at
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baseline adjusted for age, sex, socioeconomic status, smoking, alcohol abuse, and healthcare services use with increased ORs (95% CI) for anxiety (1.73 (1.23-2.41); P=0.0014), hospitalization due to anxiety (2.06 (1.25-3.40); P=0.0049), antidepressant drug use (1.46 (1.36-1.58); P<0.0001) and anxiolytic drug use (1.37 (1.27-1.48); P<0.0001) within the preceding five years. ORs for
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diagnosed depression (1.13 (0.87-1.47); P=0.3647) and hospitalization due to depression (1.32 (0.94-1.85); P=0.1083) were not increased.
We found an incidence rate (per 1,000 person-years [PY]) (95% CI) for depression of
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0.68 (0.46-1.00) for HS patients compared with 0.35 (0.35-0.36) in the background population (Table 3). Eleven events of completed suicide were observed in the HS patient population with an
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incidence rate of 0.29/1,000 PY (95% CI 0.16-0.53). The corresponding number of completed suicides in the background population was 2,904 with an incidence rate of 0.14/1,000 PY (95% CI 0.13-0.14) (Table 3).
Our fully adjusted analysis showed no increased risk (presented as hazard ratios, HR
with 95% CI) of first-time depression (1.12 (0.58-2.17); P=0.7289), hospitalization due to depression (1.61 (0.66-3.90); P=0.2947), risk of first-time anxiety (1.42 (0.73-2.74); P=0.3033), hospitalization due to anxiety (2.04 (0.84-5.00); P=0.1170) or anxiolytic drug use (1.05 (0.90-1.23);
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ACCEPTED MANUSCRIPT P=0.5455) (Table 4). The risk of completed suicide (2.42 (1.07-5.45); P=0.0334) and antidepressant drug use (1.30 (1.17-1.45); P<0.0001) were increased.
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DISCUSSION Our most predominant finding was the significantly increased risk of completed suicide in the cohort of HS patients, which remained increased even after adjustment for confounding factors. The
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increased risk may not solely be explained by demographic and lifestyle factors and the result may be seen as as a very clear indicator of how profoundly HS can affect the patients` lives. Reports on
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completed suicide among dermatological patients are far fewer than reports on suicidal ideation or depression, and in general, limited data have been published on the risk of self-harm, suicide attempts and completed suicide in patients with other common inflammatory skin diseases such as psoriasis, acne and atopic dermatitis. A recent systematic review (Chi et al., 2017) which included
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five population-based cohort studies of considered high quality (Egeberg et al., 2016b, Kimball et al., 2012, Kurd et al., 2010, Singhal et al., 2014, Wu et al., 2017) found no increase in the risk of completed suicide (risk ratio [RR] 1.13; 95% CI 0.87–1.46), suicide attempt (RR 1.25; 95% CI
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0.89–1.75), or suicidality (RR 1.26; 95% CI 0.97–1.64) among people with psoriasis. Several studies have reported a high prevalence of suicidal ideation in patients with acne, but a review on
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suicide risk in skin disorders (Picardi et al., 2013) only reported on one study investigating the risk of completed suicide in patients with severe acne (Sundstrom et al., 2010). Although the risk of completed suicide estimates were higher for patients with acne as compared with the general population in this study, the findings were nonsignificant. Similarly, an increased risk of suicidal ideation was reported in patients with atopic dermatitis (Dieris-Hirche J, 2009, Kimata, 2006, Zachariae et al., 2004), whereas the risk of completed suicide is not increased in patients with atopic dermatitis compared with the general population (Thyssen et al., 2017). These observations strongly
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ACCEPTED MANUSCRIPT suggest that our finding of increased risk of completed suicide is unique, and the results underlines the strong psychological effect of HS. In accordance with previous studies we found a higher prevalence of depression and anxiety in HS
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patients compared with the background population in our cross-sectional analysis at baseline. Adjusted ORs for association between HS and psychiatric comorbidity at baseline showed
significantly increased association with anxiety, hospitalization due to anxiety, antidepressant and
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anxiolytic drug use but no increased ORs for depression and hospitalization due to depression. Shavit et al. did find a significantly increased OR of association between depression and HS, albeit
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that the estimates were only adjusted for age and gender (Shavit et al., 2015). Using a similar approach to that of Shavit et al., we also found ORs for depression and hospitalization due to depression at baseline significantly increased. The loss of significance association in the fully adjusted analysis suggests that this increased risk can be explained by socioeconomic and lifestyle
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disparities among the two groups and may therefore be taken to reflect the socioeconomic associations of HS (Deckers et al., 2016, Theut Riis et al., 2017). However, causality cannot be inferred from cross-sectional studies and while the socioeconomic status can be an aggravating
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factor for depression, HS could also be the reason for the lower socioeconomic status. If this is the case, the socioeconomic status adjusted results might be too restrictive and the `true´rates will be
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closer to age and gender only adjusted results. In addition, our cohort study design did find a significantly increased risk of antidepressant drug use, even in fully adjusted estimates, albeit that the risk of first-time diagnosed depression or hospitalization due to depression was not significantly increased. One possible explanation for this could be that antidepressant drugs may be prescribed for milder cases of depression in the primary sector without the patient receiving a formal depression diagnosis. The significantly increased risk of antidepressant drug use is therefore a
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ACCEPTED MANUSCRIPT conceivable indication that HS patients have an increased risk of mild or moderate depression that may not require hospital treatment. Our cross-sectional analysis at baseline found an increased risk of anxiety,
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hospitalization due to anxiety and anxiolytic drug use, whereas our cohort-study did not. It may be speculated, that since HS is a chronic or recurrent disease with a significant diagnostic delay (Saunte et al., 2015), most patients who reach hospital care have a long history of HS and selection
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bias may therefore occur. Anxiety may be hypothesized to be an early phenomenon meaning that it has developed before the entry of patients into the cohort. Conversely, attrition may play a role
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since prevalent cases were excluded in the cohort study. Quality of care may also influence these results. The knowledge about the management of HS patients is rapidly increasing and was much less developed before 2008 and the lack of association in the cohort study may therefore reflect better standards of care.
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Our study revealed both an increased risk of completed suicide and indicated an increased risk of depression and anxiety among patients with HS. However, no conclusion about causality and link between these diagnoses can be made based on our results, and it should be noted
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that suicide is a symptom of a multitude of (psychiatric) diseases, not just depression and anxiety. Several important limitations apply to the interpretation of our results. Due to the
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observational design of our study, we cannot determine causality. Selection bias towards moderatesevere cases with an associated higher level of co-morbidities may play a role because of the hospital setting of selection of HS patient to the study. Misclassification may also play a role as the inclusion is based on correct ICD coding of cases.(Ingvarsson, 2017, Strunk et al., 2017) It is also a limitation that the Danish population is homogenous and predominantly white, and extrapolation of results to patients of other ethnicities should be conducted with caution.
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ACCEPTED MANUSCRIPT On the other hand, the study also has several important strengths. These include the high accuracy of the nationwide registries as well as the available information on household income, which minimized bias associated with sex, age, socioeconomic status, smoking, alcohol
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abuse and healthcare consumption. In addition, the design that combined a cross-sectional study with a cohort study providing follow-up data and the large included number in the analyses add credibility to our findings.
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In summary, we have found a significantly increased risk of completed suicide in HS patients independent of measured confounders. We have also found an increased risk of depression
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and anxiety among HS patients compared with the background population, but our further analysis indicated that this increased risk by large is explained by confounding factors. This does however not make the psychiatric comorbidities less important, and all in all the results emphasizes the inescapable importance of clinicians treating the HS patient with psychiatric comorbidities in mind.
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Ideally, this includes a structured development of strategies to prevent or minimize psychological comorbidities as well as the implementation of specific routines for clinical management. Effective assessment and treatment of psychiatric comorbidities and suicidality in HS patients with skin
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diseases depends on a multidisciplinary approach with access to a psychiatrist if needed. The use of patient reported outcomes including questionnaires for depression, anxiety and suicidal ideation in
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order to detect early stages and intervene to lower risk of progression is also recommended.
MATERIAL AND METHODS This study is one of a series of explorative epidemiological studies of HS all using a similar approach. Please see (Egeberg et al., 2016a, Egeberg et al., 2017, Theut Riis et al., 2016).
Data sources
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ACCEPTED MANUSCRIPT Ethics committee approval is not required for registry studies in Denmark, in agreement with legal requirements the study was however approved by the Danish Data Protection Agency (ref. 2007-580015, int. ref. GEH-2014-018, I-Suite 02736). The study was conducted in accordance with the
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Strengthening the Reporting of Observational Studies in Epidemiology recommendations (von Elm et al., 2007). In Denmark, the universal health care system provides the opportunities to perform population-based cohort studies. In brief, all residents are assigned a unique and permanent civil
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registration number at birth or on immigration. This unique identifier allows unambiguous linkage among all population-based administrative and health registries in the country (Schmidt et al.,
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2014). Tax-supported health care that ensures that all citizens have unrestricted access to hospitals and general practitioners. Information pertaining all patients admitted to or seen on an outpatient basis in Danish hospitals, and in some private clinics, is stored in the Danish National Patient Register, and coded in accordance with the International Classification of Diseases (ICD)( Danish
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version) (Andersen et al., 1999). In addition, all prescriptions are recorded in the Register of Medicinal Product Statistics, and classified according to the Anatomical Therapeutic Chemical (ATC) Classification System (Gaist et al., 1997). All deaths and causes of deaths are obtained from
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Larsen, 2011).
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electronic death certificates and registered in the National Causes of Death Registry (Helweg-
Study population
The study population consisted of all Danish adults (≥18 years) alive and resident in Denmark on January 1st 2008 (i.e. date of study start for all individuals in the cohort). Subjects were followed until December 31st 2012, migration, death, or the occurrence of an endpoint, whichever occurred first. All patients with a recorded diagnosis of HS (ICD-8 705.91 and ICD-10 L73.2) in the Danish National Patient Register prior to study start were classified as having HS. Tax-reported household
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ACCEPTED MANUSCRIPT income information was obtained from Statistics Denmark. The collection of the comorbidity data described in Table 1 is described elsewhere (Egeberg et al., 2016a, Egeberg et al., 2016c, Olesen et
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al., 2011).
Outcomes
The endpoints were a primary diagnosis in the Danish National Patient Register of depression (ICD-
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8 296.09, 296.29, 296.99, 298.09, 300.19, 300.49 and ICD-10 F32-33), anxiety (ICD-8 300.0, 300.2 and ICD-10 F40-41), hospitalization for depression or anxiety, a recorded completed suicide in the
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National Causes of Death Registry (ICD-10 X60–X84), respectively, as well as a claimed prescription for antidepressants (ATC N06A), or anxiolytic drugs (ATC N05B), respectively.
Statistical analysis
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Summary statistics were presented as means with standard deviation (SD) for normally distributed variables, medians and interquartile range (IQR) for non-normally distributed continuous variables and frequencies for categorical variables. The baseline period prevalence was determined as the
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percentage of individuals with one of the pre-specified diagnoses, or claimed a prescription, as appropriate, within the past five years before study start. A cross-sectional design was applied on
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January 1st 2008 using logistic regression models to assess the odds ratios (ORs) of a history of psychiatric morbidity within the past five years. Moreover, we performed a cohort study in which the entire cohort was followed from study start and until the first of either December 31st 2012, death, migration, or the occurrence of an endpoint. SAS statistical software version 9.4 (SAS Institute Inc. Cary, NC, USA) and STATA software version 13.0 (StataCorp, College Station, TX, USA) were used to summarize incidence rates per 1,000 person-years, and Cox regression models were performed to obtain HRs in the cohort study. For the cohort study, incidence was examined for
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ACCEPTED MANUSCRIPT all individuals without a history of the condition prior to study start, i.e. analyses of first-time outcome. ORs and HRs were calculated as age- and sex-adjusted, and fully adjusted (in which age, sex, socioeconomic status, smoking, alcohol abuse, and healthcare consumption were considered).
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Socioeconomic status was calculated based on the mean annual income during the 5-year period before study start, and standardized by age. Model assumptions including the proportional hazards assumption was tested and found to be valid. All statistical tests were conducted using a level of
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significance of 0.05, and results were reported with 95% CIs, where applicable.
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CONFLICT OF INTEREST
Dr. Jemec is a consultant and investigator for AbbVie and Novartis, has received unrestricted grants from Leo Pharma, and sits on the Advisory Board of AbbVie, InflaRx, Novartis, Janssen Pharmaceuticals, MSD and Pierre Fabre; and investigator for Abbvie, Novartis, Sanofi and
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Regeneron. Dr. Gislason is supported by an unrestricted research scholarship from the Novo Nordisk Foundation. Dr. Cohen has recived research grants from Novartis and has served as a consultant, advisor or speaker to Abbvie, Dexcel pharma, Janssen, Novartis, Perrigo, Pfizer and
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Rafa. Dr. Egeberg has received research funding from Pfizer and Eli Lilly, and honoraria as
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consultant and/or speaker from Pfizer, Eli Lilly, Novartis, Galderma, and Janssen Pharmaceuticals.
ACKNOWLEDSEMENTS
Author Contributions Drs. Egeberg and Gislason had full access to all of 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: Egeberg and Jemec. Acquisition, analysis, and interpretation of data: All authors. Drafting of the
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ACCEPTED MANUSCRIPT manuscript: Egeberg, Jemec, and Thorlacius. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Egeberg and Gislason. Obtained funding: None. Administrative, technical, or material support: All authors. Study supervision: Egeberg and
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Jemec.
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Scheinfeld N, Sundaram M, Teixeira H, Gu Y, Okun M. Reduction in pain scores and improvement in depressive symptoms in patients with hidradenitis suppurativa treated with adalimumab in a phase 2, randomized, placebo-controlled trial. Dermatology online journal 2016;22(3). Schmidt M, Pedersen L, Sorensen HT. The Danish Civil Registration System as a tool in epidemiology. European journal of epidemiology 2014;29(8):541-9. Shavit E, Dreiher J, Freud T, Halevy S, Vinker S, Cohen AD. Psychiatric comorbidities in 3207 patients with hidradenitis suppurativa. Journal of the European Academy of Dermatology and Venereology : JEADV 2015;29(2):371-6. Shlyankevich J, Chen AJ, Kim GE, Kimball AB. Hidradenitis suppurativa is a systemic disease with substantial comorbidity burden: a chart-verified case-control analysis. Journal of the American Academy of Dermatology 2014;71(6):1144-50. Singhal A, Ross J, Seminog O, Hawton K, Goldacre MJ. Risk of self-harm and suicide in people with specific psychiatric and physical disorders: comparisons between disorders using English national record linkage. Journal of the Royal Society of Medicine 2014;107(5):194204. Strunk A, Midura M, Papagermanos V, Alloo A, Garg A. Validation of a Case-Finding Algorithm for Hidradenitis Suppurativa Using Administrative Coding from a Clinical Database. Dermatology (Basel, Switzerland) 2017. Sundstrom A, Alfredsson L, Sjolin-Forsberg G, Gerden B, Bergman U, Jokinen J. Association of suicide attempts with acne and treatment with isotretinoin: retrospective Swedish cohort study. BMJ (Clinical research ed) 2010;341:c5812. Theut Riis P, Egeberg A, Gislason GH, Jemec GB. Patients with hidradenitis suppurativa have no increased risk of Alzheimer disease. The British journal of dermatology 2016. Theut Riis P, Thorlacius L, Knudsen List E, Jemec GBE. A pilot study of unemployment in patients with hidradenitis suppurativa in Denmark. The British journal of dermatology 2017;176(4):1083-5. Thyssen JP, Hamann CR, Linneberg A, Dantoft TM, Skov L, Gislason GH, et al. Atopic dermatitis is associated with anxiety, depression, and suicidal ideation, but not with psychiatric hospitalization or suicide. Allergy 2017. Tugnoli S, Bettoli V, Agnoli C, Caracciolo S. [Emotions and bodily experience in Hidradenitis Suppurative-Acne Inversa]. La Clinica terapeutica 2016;167(3):e55-62. Vangipuram R, Vaidya T, Jandarov R, Alikhan A. Factors Contributing to Depression and Chronic Pain in Patients with Hidradenitis Suppurativa: Results from a Single-Center Retrospective Review. Dermatology (Basel, Switzerland) 2016;232(6):692-5. 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. The Journal of investigative dermatology 2013;133(1):97-103. Vinding GR, Miller IM, Zarchi K, Ibler KS, Ellervik C, Jemec GB. The prevalence of inverse recurrent suppuration: a population-based study of possible hidradenitis suppurativa. The British journal of dermatology 2014;170(4):884-9. von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet (London, England) 2007;370(9596):1453-7. Wu JJ, Penfold RB, Primatesta P, Fox TK, Stewart C, Reddy SP, et al. The risk of depression, suicidal ideation and suicide attempt in patients with psoriasis, psoriatic arthritis or ankylosing spondylitis. Journal of the European Academy of Dermatology and Venereology : JEADV 2017;31(7):1168-75.
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TABLES
48.7 (18.0) NA
45.8 (12.2) 9.6 (4.6-16.1)
2,210,356 (50.8) 2,143,781 (49.2)
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Prevalence at baseline*, n (%) Depression Hospitalization due to depression Anxiety Hospitalization due to anxiety Antidepressant drug use Anxiolytic drug use
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Hidradenitis suppurativa (n=7,732)
5,687 (73.6) 2,045 (26.4)
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Smoking, n (%) Alcohol abuse, n (%) Diabetes, n (%) Hypertension, n (%)
General population (n=4,354,137)
871,896 (20.0) 870,665 (20.0) 870,209 (20.0) 870,440 (20.0) 870,927 (20.0)
621 (8.3) 1,673 (21.6) 2,127 (27.5) 1,901 (24.6) 1,410 (18.2)
430,882 (9.9) 60,801 (1.4) 157,662 (3.6) 527,777 (12.1)
2,055 (26.6) 201 (2.6) 532 (6.9) 942 (12.2)
35,031 (0.8) 18,783 (0.4) 13,873 (0.3) 5,651 (0.1) 787,399 (18.1) 782,482 (18.0)
126 (1.6) 72 (0.9) 64 (0.8) 28 (0.4) 2,563 (33.2) 2,297 (29.7)
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Age, mean (SD) Disease duration, median (IQR) Sex, n (%) Women Men Socioeconomic status, n (%) Lowest Below average Average Above average Highest
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Table 1 – Baseline characteristics of the study population
IQR, interquartile range; NA, not applicable; SD, standard deviation *Disease activity within past 5 years
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ACCEPTED MANUSCRIPT Table 2 –Association between hidradenitis suppurativa and psychiatric comorbidity at baseline (cross-sectional study design)
1.13
0.87-1.47
0.3647
1.32
0.94-1.85
0.1083
1.73
1.23-2.41
0.0014
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1.90
1.59-2.26 <0.0001
Hospitalization due to depression
2.06
1.63-2.60 <0.0001
Anxiety
2.34
1.83-3.00 <0.0001
Hospitalization due to anxiety
2.65
1.83-3.85 <0.0001
2.06
1.25-3.40
0.0049
Antidepressant drug use
2.19
2.09-2.30 <0.0001
1.46
1.36-1.58 <0.0001
Anxiolytic drug use
2.02
1.92-2.13 <0.0001
1.37
1.27-1.48 <0.0001
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Depression
Fully adjusted* Odds ratio 95% CI p-value
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Age- and sex adjusted Odds ratio 95% CI p-value
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CI, confidence interval *Adjusted for age, sex, socioeconomic status, smoking, alcohol abuse, and healthcare consumption
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ACCEPTED MANUSCRIPT Table 3 – Summary of number of new events, follow-up time, and incidence rates of the study outcomes per 1,000 person-years General population Hidradenitis suppurativa Depression Follow-up time, years Number of events Incidence rate/1,000 PY (95% CI)
20,707,731 7,317 0.35 (0.35-0.36)
Hospitalization due to depression Follow-up time, years Number of events Incidence rate/1,000 PY (95% CI)
20,792,968 2,696 0.13 (0.12-0.13)
Anxiety Follow-up time, years Number of events Incidence rate/1,000 PY (95% CI)
20,806,412 4,572 0.22 (0.21-0.23)
37,249 15 0.40 (0.24-0.67)
20,853,061 1,707 0.08 (0.08-0.09)
37,451 9 0.24 (0.13-0.46)
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Hospitalization due to anxiety Follow-up time, years Number of events Incidence rate/1,000 PY (95% CI)
36,940 25 0.68 (0.46-1.00)
20,882,557 2,904 0.14 (0.13-0.14)
37,611 11 0.29 (0.16-0.53)
Antidepressant drug use Follow-up time, years Number of events Incidence rate/1,000 PY (95% CI)
16,465,559 313,029 19.01 (18.94-19.08)
23,186 802 34.59 (32.28-37.07)
16,933,337 149,563 8.83 (8.79-8.88)
25,854 336 13.00 (11.68-14.46)
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Suicide Follow-up time, years Number of events Incidence rate/1,000 PY (95% CI)
Anxiolytic drug use Follow-up time, years Number of events Incidence rate/1,000 PY (95% CI)
CI, confidence interval; PY, person-years
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ACCEPTED MANUSCRIPT Table 4 – Hazard ratios for risk of first-time depression, anxiety, antidepressant or anxiolytic drug use, and completed suicide, respectively, among patients with hidradenitis suppurativa compared with the general population (cohort study design) Fully adjusted* Hazard ratio 95% CI p-value
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Age- and sex adjusted Hazard ratio 95% CI p-value 2.08
1.40-3.08 0.0003
1.12
0.58-2.17 0.7289
Hospitalization due to depression
2.18
1.13-4.19 0.0200
1.61
0.66-3.90 0.2947
Anxiety
1.63
0.98-2.70 0.0595
1.42
0.73-2.74 0.3033
Hospitalization due to anxiety
2.74
1.42-5.28 0.0026
2.04
0.84-5.00 0.1170
Completed suicide
2.89
1.60-5.23 0.0004
2.42
1.07-5.45 0.0334
Antidepressant drug use
1.74
1.62-1.86 <0.0001
1.30
1.17-1.45 <0.0001
Anxiolytic drug use
1.54
1.38-1.71 <0.0001
1.05
0.90-1.23 0.5455
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Depression
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CI, confidence interval *Adjusted for age, sex, socioeconomic status, smoking, alcohol abuse, and healthcare consumption
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