- Email: [email protected]
Prevalence and Risk of Inflammatory Bowel Disease in Patients with Hidradenitis Suppurativa
Accepted Manuscript Prevalence and risk of inflammatory bowel disease in patients with hidradenitis suppurativa Alexander Egeberg, MD, PhD, Gregor B.E. Jemec, MD, DMSc, Alexa B. Kimball, MD MPH, Hervé Bachelez, MD, Gunnar H. Gislason, MD, PhD, Jacob P. Thyssen, MD, PhD, DMSc, Lotus Mallbris, MD, PhD PII:
S0022-202X(17)30011-8
DOI:
10.1016/j.jid.2016.11.040
Reference:
JID 685
To appear in:
The Journal of Investigative Dermatology
Received Date: 17 October 2016 Revised Date:
11 November 2016
Accepted Date: 28 November 2016
Please cite this article as: Egeberg A, Jemec GBE, Kimball AB, Bachelez H, Gislason GH, Thyssen JP, Mallbris L, Prevalence and risk of inflammatory bowel disease in patients with hidradenitis suppurativa, The Journal of Investigative Dermatology (2017), doi: 10.1016/j.jid.2016.11.040. 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
Title Page
2
Title
3
Prevalence and risk of inflammatory bowel disease in patients with hidradenitis suppurativa
4
Manuscript word, table and figure count
5
2352 words, 4 tables, 1 figure
6
Authors full names, departments, and institutions
7
Alexander Egeberg1 MD, PhD; Gregor B.E. Jemec2 MD, DMSc; Alexa B. Kimball3 MD MPH; Hervé
8
Bachelez4 MD; Gunnar H. Gislason5,6,7 MD, PhD; Jacob P. Thyssen1 MD, PhD, DMSc; Lotus Mallbris8 MD,
9
PhD
M AN U
SC
RI PT
1
1) Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen,
11
Hellerup, Denmark
12
2) Department of Dermatology, Zealand University Hospital, Roskilde; University of Copenhagen, Denmark
13
3) Department of Dermatology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston,
14
Massachusetts, United States
15
4) Department of Dermatology, AP-HP Hôpital Saint-Louis; Sorbonne Paris Cité Université Paris Diderot;
16
INSERM U1163, Imagine Institute, Necker Hospital, Paris, France
17
5) Department of Cardiology, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
18
6) The Danish Heart Foundation, Copenhagen, Denmark
19
7) The National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark
20
8) Eli Lilly and Company, Indianapolis, Indiana, United States
21
Corresponding author
AC C
EP
TE D
10
Page 1 of 21
ACCEPTED MANUSCRIPT Alexander Egeberg, Department of Dermatology and Allergy, Herlev and Gentofte Hospital, Kildegårdsvej
23
28, 2900 Hellerup, Denmark
24
Telephone:
(0045) 24215421
25
E-mail:
[email protected]
RI PT
22
AC C
EP
TE D
M AN U
SC
26
Page 2 of 21
Abbreviations
28
CD
Crohn’s disease
29
HR
Hazard ratio
30
IBD
Inflammatory bowel disease
31
ICD
International Classification of Diseases
32
IL
Interleukin
33
OR
Odds ratio
34
SD
Standard deviation
35
TNF
Tumor necrosis factor
36
UC
Ulcerative colitis
M AN U
SC
27
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
37
Page 3 of 21
ACCEPTED MANUSCRIPT
Abstract
39
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease. In small studies, inflammatory bowel
40
disease (IBD) has been associated with increased prevalence of HS, but data on the concurrence of IBD in
41
patients with HS is limited. We therefore investigated the prevalence and risk of IBD in patients with HS
42
compared with the general population. The study linked all Danish individuals ≥18 years in nationwide
43
registers. Adjusted odds ratios (OR) and adjusted hazard ratios (HRs) were estimated by logistic regression
44
and Cox regression, respectively. The study comprised 7,732 patients with HS, and 4,354,137 subjects from
45
the general population. The prevalence (HS vs. general population) was 0.8% and 0.3% (OR 2.04; 1.59-2.62)
46
for CD and 1.3% and 0.7% (OR 1.75; 1.44-2.13) for UC. The risk of new-onset CD (HR 2.19; 1.44-3.34)
47
and UC (HR 1.63; 1.18-2.27) was significantly increased among patients with HS. In conclusion, HS was
48
significantly associated with presence and risk of new-onset IBD, although the prevalence remained low.
49
Gastrointestinal complaints in patients with HS should warrant further clinical examination.
M AN U
SC
RI PT
38
AC C
EP
TE D
50
Page 4 of 21
ACCEPTED MANUSCRIPT
Introduction
52
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease, characterized by painful recurrent,
53
suppurating and malodorous abscesses in areas rich with apocrine sweat glands, such as the axillae and
54
genital area.(Jemec, 2012) European studies have suggested a HS prevalence of 1-4% with a 3:1 female
55
preponderance, and the disease usually develops in subjects in their early twenties.(Jemec, 2012) The
56
psychosocial burden and negative impact of HS on quality of life is greater than that of other dermatological
57
conditions and the disease is likely to be both under-diagnosed and frequently associated with a 5-10 year-
58
long diagnostic delay.(Dufour et al., 2014, Jemec, 2012, Onderdijk et al., 2013, von der Werth and Jemec,
59
2001, Wolkenstein et al., 2007) Although the etiopathogenesis of HS is not fully understood, studies have
60
suggested the combination of a dysregulation of pilosebaceous unit homeostasis with cysts formation, and
61
dysregulated immune responses leading to chronic inflammation, with an assumed contribution of the
62
bacterial environment..(Kelly et al., 2015, Micheletti, 2014, Schlapbach et al., 2011, van der Zee et al., 2011)
63
Indeed, increased expression of inflammatory cytokines such as interleukin (IL)-1β, IL-10, IL-17, and tumor
64
necrosis factor (TNF)-α has been demonstrated in HS lesions and reports of elevated circulating levels of
65
TNF-α are suggestive of systemic inflammatory activation.(Kellyet al., 2015, Matusiak et al., 2009,
66
Schlapbachet al., 2011, van der Zeeet al., 2011) Indeed, a study of 50 Danish outpatient hospital patients
67
with HS and 250 matched controls from the same dermatology clinic found that patients with HS carry a
68
higher systemic inflammatory load, with higher circulating leukocyte counts and C-reactive protein levels
69
than, e.g., patients with psoriasis.(Riis et al., 2015)
70
Crohn’s disease (CD) and ulcerative colitis (UC) are the two predominant types of chronic relapsing
71
inflammatory disorders of the gastrointestinal tract, collectively referred to as inflammatory bowel disease
72
(IBD).(Abraham and Cho, 2009) Although CD and UC are immunologically and demographically different,
73
the two conditions can sometimes be hard to distinguish in early presentation. Dysregulation of the
74
gastrointestinal immune system in genetically predisposed individuals is believed to play an important part in
75
the pathogenesis of IBD.(Abraham and Cho, 2009) Interestingly, HS and IBD share numerous similarities
AC C
EP
TE D
M AN U
SC
RI PT
51
Page 5 of 21
ACCEPTED MANUSCRIPT suggestive of a shared pathogenesis. For example, smoking has been shown to be a worsening factor in HS
77
as well as in IBD.(Nazary et al., 2011, Rosenfeld and Bressler, 2012) Moreover, both HS and CD are
78
characterized by scarring and sinus tract formation,(Baumgart and Sandborn, 2007, Jemec, 2012) and Th-17
79
cells, IL-23 and TNF appear to be involved in HS as well as IBD.(Duerr et al., 2006, Schlapbachet al., 2011)
80
Along this line, certain genes e.g. SULT1B1 and SULT1E1 have been associated with HS as well as
81
IBD.(Janse et al., 2016)
82
While studies have suggested a link between HS and IBD, results are inconsistent and the association
83
remains poorly understood.(Principi et al., 2016, Shalom et al., 2016, van der Zee et al., 2014, van der Zee et
84
al., 2010, Yadav et al., 2016) We therefore examined the prevalence, co-occurrence, and risk of new-onset
85
IBD in patients with HS, using a nationwide cohort of the Danish population.
M AN U
SC
RI PT
76
86
Results
88
The study cohort comprised a total of 7,732 patients with a hospital (inpatient or ambulatory) diagnosis of
89
HS, and 4,354,137 general population control subjects. A strong female predominance (73.6%) was observed
90
among patients with HS, and smoking was significantly more frequent compared with the reference
91
population (p<0.0001). At baseline, the period prevalence (from 1978 until 2008) of CD was 0.3% and 0.8%
92
(Table 1, and Figure 1) in the reference population and in patients with HS, respectively, yielding an adjusted
93
OR of 2.04 (1.59-2.62; risk difference 0.003) (Table 2). Similarly, the prevalence of UC was 0.7% and 1.3%,
94
respectively, with an adjusted OR of 1.75 (1.44-2.13; risk difference 0.002). For patients with co-occurring
95
diagnosis of CD and UC (‘unspecified IBD’), the prevalence was 0.1% and 0.7%, respectively (adjusted OR
96
3.40; 2.60-4.44; risk difference 0.007). In cases where IBD preceded the onset of HS, the mean time from
97
IBD to HS was 8.5 (SD 7.3) years, whereas the mean time from HS to IBD was 9.7 (SD 7.9) years when HS
98
occurred first. During follow-up, a total of 4,001 and 22 patients developed new-onset CD, among the
99
reference population and patients with HS, respectively. Similarly, there were 10,359 and 36 cases of UC,
100
and 1,016 and 5 cases of unspecified IBD, respectively, during follow-up (Table 3). After adjustment for
AC C
EP
TE D
87
Page 6 of 21
ACCEPTED MANUSCRIPT potential confounding factors, the fully adjusted HR associated with HS was 2.19 (1.44-3.34) for CD, 1.63
102
(1.18-2.27) for UC, and 2.07 (0.86-5.00; p=0.1052 for unspecified IBD (Table 4). In sensitivity analyses,
103
additional adjustment of use of tetracycline class agents did not significantly alter any of the results
104
compared with our primary analyses (data not shown).
105
Discussion
106
In this nationwide study of the Danish population, we found that HS was associated with a significantly
107
increased risk of co-occurring and new-onset IBD, with a prevalence ranging from 0.7% to 1.3%, and an
108
incidence of 0.13 to 0.97 per 1,000 HS-patients per year.
109
Previous studies have reported vast discrepancies on the co-occurrence of HS and IBD. For example, in a
110
Dutch study,(Yadavet al., 2016) the prevalence of HS was 23% (n=223/1093) in a cohort of patients with
111
IBD, with higher prevalence for CD than UC.(van der Zeeet al., 2014) On the other hand, a population-based
112
study from Minnesota found a HS point prevalence of 1.2% (n=8/679) among patients with IBD, with an
113
incidence rate ratio of 8.9 (95% CI 3.6-17.5). While the majority of studies have examined the concurrence
114
of HS in IBD populations, one Israeli cross-sectional study (Shalomet al., 2016) of 3,207 patients with HS,
115
and 6,412 age- and sex-matched healthy control subjects reported an increased prevalence and risk of CD
116
(0.8% vs. 0.4%; adjusted OR 2.03; 95% CI 1.14-3.62) and UC (0.4% vs. 0.2%; adjusted OR 1.82; 95% CI
117
0.81-4.05), albeit that the latter did not reach statistical significance. Nevertheless, the adjusted estimates
118
appear to be in line with the findings from our cohort. Moreover, one very recent study from the Netherlands
119
found a 2.5% and 0.8% prevalence of CD and UC, respectively, among patients with HS.(Deckers et al.,
120
2016) To our knowledge, the present cohort is the largest study of prevalence and risk of IBD in patients
121
with pre-existing HS, and the findings expands the existing literature considerably by suggesting an
122
augmented prevalence and risk of new-onset IBD in patients with HS.
123
Several hypotheses have been put forward to potentially explain the link between HS and IBD. For example,
124
chronic gastrointestinal inflammation in IBD may result from abnormal immune responses to gut
125
microorganisms in genetically susceptible individuals.(Maloy and Powrie, 2011) Moreover, smoking plays
AC C
EP
TE D
M AN U
SC
RI PT
101
Page 7 of 21
ACCEPTED MANUSCRIPT an important role in HS as well as IBD.(Nazaryet al., 2011, Rosenfeld and Bressler, 2012) A history of
127
smoking was higher among patients with HS in our cohort, and while smoking may aggravate CD, it appears
128
to have beneficial effects on UC.(van der Heide et al., 2009) Shared genetic risk loci may also play a
129
role,(Janseet al., 2016, van der Zee et al., 2016) and while pro-inflammatory cytokines are upregulated in
130
HS,(Schlapbachet al., 2011) treatment with anti-TNF agents have shown promise in management of
131
HS.(Kimball et al., 2016). Finally, an increased prevalence of spondylarthropathy has been reported in
132
patients with IBD as well as in those with HS, raising the hypothesis that genetic, epigenetic and/or
133
environmental factors cooperate to lead to dysregulated inflammatory pathways across these immune-
134
mediated diseases.(Gionchetti et al., 2015, Richette et al., 2014)
135
Certain limitations apply to the interpretation of the present study. Due to the observational nature of our
136
study we cannot determine causality. We were unable to distinguish between severities of HS, and
137
while patients with HS in our study were identified by hospital diagnosis, studies have suggested
138
that patients with HS seen in hospital settings have more comorbidity than HS patients sampled
139
from a population setting.(Tzellos et al., 2015) Furthermore, although our endpoint was previously
140
validated, it has been suggested that HS may be misdiagnosed as cutaneous CD,(van der Zeeet al.,
141
2016) and we cannot refute that some misclassification could have occurred in this regard. Also,
142
while dichotomous proxy data on smoking and alcohol abuse were available, the lack of
143
quantitative data on (e.g. number of cigarettes or grams of alcohol per day) could have biased our
144
estimates. Lastly, the Danish population is predominantly of Northern European descent, and
145
extrapolation of results to patients with other ethnicities should be carried out with caution.
146
In conclusion, we found an increased prevalence and risk of new-onset CD and UC in patients with HS. The
147
link may be due to a shared immuno-pathogenesis, as well as modifiable life-style factors. In HS patients
148
presenting with gastrointestinal complaints, timely referral for gastroenterological evaluation of IBD may be
149
appropriate.
AC C
EP
TE D
M AN U
SC
RI PT
126
Page 8 of 21
ACCEPTED MANUSCRIPT
Materials and methods
151
Data sources and study population
152
Study approval was obtained from the Danish Data Protection Agency (ref. 2007-58-0015, int. ref. GEH-
153
2014-018, I-Suite 02736), and approval from an ethics committee is not required for registry studies in
154
Denmark. The study was conducted in accordance with the Strengthening the Reporting of Observational
155
Studies in Epidemiology recommendations.(von Elm et al., 2007)
156
Using the unique personal identification number assigned to all Danish citizens, we linked individual-level-
157
information from nationwide administrative registers. The Civil Registration System(Schmidt et al., 2014)
158
contains information on sex, date of birth, and updated information on vital status and emigration, thus
159
minimizing loss to follow-up. All in- and outpatient (ambulatory) hospital consultations are recorded in the
160
Danish National Patient Register(Andersen et al., 1999) (DNPR) including 1 primary and up to 19 secondary
161
diagnoses coded by discharging physicians according to the International Classification of Diseases, eighth
162
revision (ICD-8) (prior to 1994), and according to the tenth revision (ICD-10) thereafter. The primary
163
diagnosis is the main reason for the hospital consultation or hospitalization, and secondary diagnoses are
164
additional conditions, including complications. Since 1994, detailed and accurate information on all
165
pharmacy-dispensed medications has been registered in the Danish Registry of Medicinal Products
166
Statistics.(Gaist et al., 1997) Information on tax-reported household income is recorded by Statistics
167
Denmark.(Baadsgaard and Quitzau, 2011)
SC
M AN U
TE D
EP
AC C
168
RI PT
150
169
We identified all Danish adults (≥18 years) alive and resident in Denmark on January 1st 2008 (i.e. date of
170
study start for all individuals in the cohort). Subjects were followed from study start and until December 31st
171
2012, death, migration, or the occurrence of an endpoint, whichever came first. Patients were classified as
172
having HS if they prior to study start had received a diagnosis (inpatient or ambulatory) of HS (ICD-8 705.91
173
and ICD-10 L73.2) recorded in the DNPR. Collection of data on diabetes, hypertension, smoking history,
174
and alcohol abuse has been described elsewhere.(Egeberg et al., 2016a, Egeberg et al., 2016b, Olesen et al.,
Page 9 of 21
ACCEPTED MANUSCRIPT 2011) From Statistics Denmark we used information on tax-reported household income to calculate an age-
176
standardized index of socioeconomic status based on the mean gross annual income during a 5-year period
177
before study start.
178
Patients with IBD were defined as both hospitalized patients and patients in outpatient clinical settings who
179
had a recorded diagnosis of CD (ICD-8 codes 563.00–563.09 or ICD-10 code group K50) or UC (ICD-8
180
codes 563.19 or 569.04, or ICD-10 code group K51). Patients with concurrent diagnoses of both CD and UC
181
were characterized as having “unspecified IBD”, as these conditions may be subject to diagnostic overlap.
182
The completeness of IBD diagnoses from the DNPR was previously evaluated to be 94%, by comparing a
183
pathology database as reference, whereas the validity was 97% for CD and 90% for UC.(Fonager et al.,
184
1996)
M AN U
SC
RI PT
175
185 Statistical analysis
187
We described baseline characteristics with means and standard deviations for continuous variables and
188
frequencies and percentages for categorical variables. The baseline prevalence of IBD was determined as the
189
percentage of individuals which had received a diagnosis of CD or UC between January 1st 1978 (when the
190
DNPR was established) and January 1st 2008 (the study start date). SAS statistical software version 9.4 (SAS
191
Institute Inc. Cary, NC, USA) and STATA software version 13.0 (StataCorp, College Station, TX, USA)
192
were used to summarize incidence rates per 1,000 person-years, and Cox regression models were performed
193
to obtain hazard ratios (HRs) for the risk of incident IBD, whereas odds ratios (ORs) were calculated based
194
on logistic regression. Incidence of IBD during follow-up was calculated for all individuals without a history
195
of IBD prior to study start. HRs for IBD were calculated as age- and sex-adjusted, and fully adjusted (in
196
which age, sex, socioeconomic status, smoking, alcohol abuse, and healthcare consumption [number of clinic
197
visits] were considered). Since studies have suggested that tetracycline class agents, i.e. drugs frequently
198
used in treatment of HS, may influence the onset of IBD,(Margolis et al., 2010) we performed sensitivity
199
analyses adjusted for use of such drugs. Model assumptions were tested and found to be valid unless
AC C
EP
TE D
186
Page 10 of 21
ACCEPTED MANUSCRIPT otherwise specified. Two-tailed p-values less than 0.05 were considered statistically significant and results
201
were reported with 95% confidence intervals (CIs) where applicable.
202
Author Contributions
203
Drs. Egeberg and Gislason had full access to all of the data in the study and take responsibility for the
204
integrity of the data and the accuracy of the data analysis. Study concept and design: Egeberg. Acquisition,
205
analysis, and interpretation of data: All authors. Drafting of the manuscript: Egeberg. Critical revision of
206
the manuscript for important intellectual content: All authors. Statistical analysis: Egeberg and Gislason.
207
Obtained funding: Egeberg and Mallbris. Administrative, technical, or material support: Egeberg, Gislason,
208
and Thyssen. Study supervision: Egeberg and Gislason.
209
Declaration of interests
210
Dr. Egeberg has received research funding from Pfizer and Eli Lilly, and honoraria as consultant and/or
211
speaker from Pfizer, Eli Lilly, Novartis, Galderma, and Janssen Pharmaceuticals. Dr. Bachelez has received
212
consultancy and/or speaker honoraria from Abbvie, Amgen, Boehringer Ingelheim, Baxalta, Bayer, Celgene,
213
Janssen Pharmaceuticals, Leo Pharma, Eli Lilly, Novartis, Janssen-Cilag, Merck Sharp & Dohme, Pfizer,
214
Sandoz, Takeda, and grant support by Pfizer. Dr. Kimball received honoraria for serving as a consultant for
215
AbbVie, Dermira, Eli Lilly, Merck, Novartis, and Pfizer; received residency and fellowship program funding
216
from Janssen Pharmaceuticals; and received grant/research funding as an investigator for Abbott
217
Laboratories, Amgen, Dermira, Janssen, Merck, and Novartis. Dr. Gislason is supported by an unrestricted
218
research scholarship from the Novo Nordisk Foundation. Dr. Jemec is a consultant and investigator for
219
AbbVie and Novartis, has received unrestricted grants from Leo Pharma, and sits on the Advisory Board of
220
AbbVie, Novartis, Janssen Pharmaceuticals and MSD; and investigator for Regeneron. Dr. Mallbris is
221
currently employed by Eli Lilly and Company.
222
Funding sources
223
Eli Lilly and Company
AC C
EP
TE D
M AN U
SC
RI PT
200
Page 11 of 21
ACCEPTED MANUSCRIPT Funding/Sponsor was involved?
225
Design and conduct of the study
Yes ___
No _X_
226
Collection, management, analysis and interpretation of data
Yes _X_
No __
227
Preparation, review, or approval of the manuscript
Yes _X_
No __
228
Decision to submit the manuscript for publication
Yes _X_
No __
229
The funding sources participated in interpretation of the final analyzed study results, but had no access to the
230
raw data, and did not participate in data collection, management, or analysis.
AC C
EP
TE D
M AN U
SC
RI PT
224
Page 12 of 21
ACCEPTED MANUSCRIPT 231
Reference list
232 Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med 2009;361(21):2066-78.
234
Andersen TF, Madsen M, Jorgensen J, Mellemkjoer L, Olsen JH. The Danish National Hospital Register. A
237 238 239 240
Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet 2007;369(9573):1641-57.
Baadsgaard M, Quitzau J. Danish registers on personal income and transfer payments. Scand J Public Health
SC
236
valuable source of data for modern health sciences. Dan Med Bull 1999;46(3):263-8.
2011;39(7 Suppl):103-5.
Deckers IE, Benhadou F, Koldijk MJ, Del Marmol V, Horvath B, Boer J, et al. Inflammatory bowel disease
M AN U
235
RI PT
233
241
is associated with hidradenitis suppurativa: Results from a multicenter cross-sectional study. Journal
242
of the American Academy of Dermatology 2016.
244 245
Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006;314(5804):1461-3.
TE D
243
Dufour DN, Emtestam L, Jemec GB. Hidradenitis suppurativa: a common and burdensome, yet underrecognised, inflammatory skin disease. Postgraduate medical journal 2014;90(1062):216-21; quiz
247
20.
249 250
Egeberg A, Gislason G, Hansen P. Risk of major adverse cardiovascular events and all-cause mortality in patients with hidradenitis suppurativa. JAMA dermatology 2016a;152(4):1-6.
AC C
248
EP
246
Egeberg A, Mallbris L, Gislason GH, Skov L, Hansen PR. Risk of Multiple Sclerosis in Patients with
251
Psoriasis: A Danish Nationwide Cohort Study. The Journal of investigative dermatology
252
2016b;136(1):93-8.
253
Fonager K, Sorensen HT, Rasmussen SN, Moller-Petersen J, Vyberg M. Assessment of the diagnoses of
254
Crohn's disease and ulcerative colitis in a Danish hospital information system. Scandinavian journal
255
of gastroenterology 1996;31(2):154-9.
256
Gaist D, Sorensen HT, Hallas J. The Danish prescription registries. Dan Med Bull 1997;44(4):445-8.
Page 13 of 21
ACCEPTED MANUSCRIPT 257 258 259
Gionchetti P, Calabrese C, Rizzello F. Inflammatory Bowel Diseases and Spondyloarthropathies. J Rheumatol Suppl 2015;93:21-3. Janse IC, Koldijk MJ, Spekhorst LM, Vila AV, Weersma RK, Dijkstra G, et al. Identification of Clinical and Genetic Parameters Associated with Hidradenitis Suppurativa in Inflammatory Bowel Disease.
261
Inflammatory bowel diseases 2016;22(1):106-13.
RI PT
260
262
Jemec GB. Clinical practice. Hidradenitis suppurativa. N Engl J Med 2012;366(2):158-64.
263
Kelly G, Hughes R, Mc Garry T, van den Born M, Adamzik K, Fitzgerald R, et al. Dysregulated cytokine
266 267 268 269
SC
265
expression in lesional and non-lesional skin in Hidradenitis suppurativa. Br J Dermatol 2015. Kimball AB, Okun MM, Williams DA, Gottlieb AB, Papp KA, Zouboulis CC, et al. Two Phase 3 Trials of Adalimumab for Hidradenitis Suppurativa. N Engl J Med 2016;375(5):422-34.
M AN U
264
Maloy KJ, Powrie F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 2011;474(7351):298-306.
Margolis DJ, Fanelli M, Hoffstad O, Lewis JD. Potential association between the oral tetracycline class of antimicrobials used to treat acne and inflammatory bowel disease. The American journal of
271
gastroenterology 2010;105(12):2610-6.
272
TE D
270
Matusiak L, Bieniek A, Szepietowski JC. Increased serum tumour necrosis factor-alpha in hidradenitis suppurativa patients: is there a basis for treatment with anti-tumour necrosis factor-alpha agents?
274
Acta dermato-venereologica 2009;89(6):601-3.
276 277 278 279
Micheletti RG. Hidradenitis suppurativa: current views on epidemiology, pathogenesis, and pathophysiology. Semin Cutan Med Surg 2014;33(3 Suppl):S48-50.
AC C
275
EP
273
Nazary M, van der Zee HH, Prens EP, Folkerts G, Boer J. Pathogenesis and pharmacotherapy of Hidradenitis suppurativa. Eur J Pharmacol 2011;672(1-3):1-8. Olesen JB, Lip GY, Hansen ML, Hansen PR, Tolstrup JS, Lindhardsen J, et al. Validation of risk
280
stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation:
281
nationwide cohort study. BMJ 2011;342:d124.
282 283
Onderdijk AJ, van der Zee HH, Esmann S, Lophaven S, Dufour DN, Jemec GB, et al. Depression in patients with hidradenitis suppurativa. J Eur Acad Dermatol Venereol 2013;27(4):473-8.
Page 14 of 21
ACCEPTED MANUSCRIPT 284
Principi M, Cassano N, Contaldo A, Iannone A, Losurdo G, Barone M, et al. Hydradenitis suppurativa and
285
inflammatory bowel disease: An unusual, but existing association. World J Gastroenterol
286
2016;22(20):4802-11.
287
Richette P, Molto A, Viguier M, Dawidowicz K, Hayem G, Nassif A, et al. Hidradenitis suppurativa associated with spondyloarthritis -- results from a multicenter national prospective study. The
289
Journal of rheumatology 2014;41(3):490-4.
292 293 294 295 296 297
inflammatory load than other dermatological patients. Arch Dermatol Res 2015.
SC
291
Riis PT, Soeby K, Saunte DM, Jemec GB. Patients with hidradenitis suppurativa carry a higher systemic
Rosenfeld G, Bressler B. The truth about cigarette smoking and the risk of inflammatory bowel disease. The American journal of gastroenterology 2012;107(9):1407-8.
M AN U
290
RI PT
288
Schlapbach C, Hanni T, Yawalkar N, Hunger RE. Expression of the IL-23/Th17 pathway in lesions of hidradenitis suppurativa. Journal of the American Academy of Dermatology 2011;65(4):790-8. Schmidt M, Pedersen L, Sorensen HT. The Danish Civil Registration System as a tool in epidemiology. Eur J Epidemiol 2014;29(8):541-9.
Shalom G, Freud T, Ben Yakov G, Khoury R, Dreiher J, Vardy DA, et al. Hidradenitis Suppurativa and
299
Inflammatory Bowel Disease: A Cross-Sectional Study of 3,207 Patients. The Journal of
300
investigative dermatology 2016;136(8):1716-8.
TE D
298
Tzellos T, Zouboulis CC, Gulliver W, Cohen AD, Wolkenstein P, Jemec GB. Cardiovascular disease risk
302
factors in patients with hidradenitis suppurativa: a systematic review and meta-analysis of
303
observational studies. Br J Dermatol 2015.
AC C
304
EP
301
van der Heide F, Dijkstra A, Weersma RK, Albersnagel FA, van der Logt EM, Faber KN, et al. Effects of
305
active and passive smoking on disease course of Crohn's disease and ulcerative colitis. Inflammatory
306
bowel diseases 2009;15(8):1199-207.
307
van der Zee HH, de Ruiter L, van den Broecke DG, Dik WA, Laman JD, Prens EP. Elevated levels of
308
tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-10 in hidradenitis suppurativa
309
skin: a rationale for targeting TNF-alpha and IL-1beta. Br J Dermatol 2011;164(6):1292-8.
Page 15 of 21
ACCEPTED MANUSCRIPT 310 311 312
van der Zee HH, de Winter K, van der Woude CJ, Prens EP. The prevalence of hidradenitis suppurativa in 1093 patients with inflammatory bowel disease. Br J Dermatol 2014;171(3):673-5. van der Zee HH, Horvath B, Jemec GB, Prens EP. The Association between Hidradenitis Suppurativa and Crohn's Disease: in Search of the Missing Pathogenic Link. The Journal of investigative
314
dermatology 2016;136(9):1747-8.
316 317 318
van der Zee HH, van der Woude CJ, Florencia EF, Prens EP. Hidradenitis suppurativa and inflammatory bowel disease: are they associated? Results of a pilot study. Br J Dermatol 2010;162(1):195-7. von der Werth JM, Jemec GB. Morbidity in patients with hidradenitis suppurativa. Br J Dermatol
SC
315
RI PT
313
2001;144(4):809-13.
von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP, et al. The Strengthening the
320
Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting
321
observational studies. Lancet 2007;370(9596):1453-7.
322
M AN U
319
Wolkenstein P, Loundou A, Barrau K, Auquier P, Revuz J, Quality of Life Group of the French Society of D. Quality of life impairment in hidradenitis suppurativa: a study of 61 cases. J Am Acad Dermatol
324
2007;56(4):621-3.
325
TE D
323
Yadav S, Singh S, Edakkanambeth Varayil J, Harmsen WS, Zinsmeister AR, Tremaine WJ, et al. Hidradenitis Suppurativa in Patients With Inflammatory Bowel Disease: A Population-Based Cohort
327
Study in Olmsted County, Minnesota. Clin Gastroenterol Hepatol 2016;14(1):65-70.
329
AC C
328
EP
326
Page 16 of 21
ACCEPTED MANUSCRIPT 330
Table 1 – Baseline characteristics of the study population Reference population Hidradenitis suppurativa (n=4,354,137) (n=7,732)
Smoking, n (%) Alcohol abuse, n (%) Diabetes, n (%) Hypertension, n (%)
5,687 (73.6) 2,045 (26.4)
621 (8.3) 1,673 (21.6) 2,127 (27.5) 1,901 (24.6) 1,410 (18.2)
SC
871,896 (20.0) 870,665 (20.0) 870,209 (20.0) 870,440 (20.0) 870,927 (20.0)
RI PT
45.8 (12.2) 9.6 (4.6-16.1)
2,210,356 (50.8) 2,143,781 (49.2)
350,870 (8.1) 60,801 (1.4) 157,662 (3.6) 527,777 (12.1)
1,724 (22.3) 201 (2.6) 532 (6.9) 942 (12.2)
12,667 (0.3) 29,843 (0.7) 6,427 (0.1)
63 (0.8) 103 (1.3) 55 (0.7)
TE D
Prevalent IBD at baseline, n (%) Crohn's disease Ulcerative colitis Unspecified IBD
48.7 (18.0) NA
M AN U
Age, mean (SD) Disease duration, median (IQR) Sex, n (%) Women Men Socioeconomic status, n (%) Lowest Below average Average Above average Highest
332
AC C
331
EP
IBD, inflammatory bowel disease; IQR, interquartile range; NA, not applicable; SD, standard deviation
Page 17 of 21
ACCEPTED MANUSCRIPT 333
Table 2 – Odds ratios for association between hidradenitis suppurativa and inflammatory bowel
334
disease at baseline (cross-sectional study design) Fully adjusted* OR 95% CI p-value
Crohn's disease
2.61
2.03-3.34
<0.0001
2.04 1.59-2.62 <0.0001
Ulcerative colitis
1.96
1.61-2.37
<0.0001
1.75 1.44-2.13 <0.0001
Unspecificed IBD
4.50
3.45-5.88
<0.0001
3.40 2.60-4.44 <0.0001
SC
RI PT
Hidradenitis suppurativa
Age- and sex-adjusted OR 95% CI p-value
M AN U
OR, Odds ratio; CI, confidence interval; IBD, inflammatory bowel disease *age, sex, socioeconomic status, healthcare consumption, smoking and alcohol abuse 335
336
337
AC C
EP
TE D
338
Page 18 of 21
ACCEPTED MANUSCRIPT 339
Table 3 – Summary of number of new events, follow-up time, and incidence rates of inflammatory
340
bowel disease per 1,000 person-years
New-onset ulcerative colitis Follow-up time, years Number of events Incidence rate/1,000 PY 95% CI
20,714,056 10,359 0.50 0.49-0.51
20,848,622 1,016 0.05 0.05-0.05
37,015 36 0.97 0.70-1.35
37,326 5 0.13 0.06-0.32
TE D
New-onset unspecified IBD Follow-up time, years Number of events Incidence rate/1,000 PY 95% CI
37,240 22 0.59 0.39-0.90
SC
20,812,454 4,001 0.19 0.19-0.19
M AN U
New-onset Crohn's disease Follow-up time, years Number of events Incidence rate/1,000 PY 95% CI
RI PT
Reference population Hidradenitis suppurativa
343
AC C
342
EP
CI, confidence interval; PY, person-years 341
Page 19 of 21
ACCEPTED MANUSCRIPT 344
Table 4 – Hazard ratios for risk of new-onset inflammatory bowel disease among patients with
345
hidradenitis suppurativa compared with the general population (cohort study design)
2.83 (1.86-4.30) 2.19 (1.44-3.34)
Ulcerative colitis Age- and sex-adjusted Fully adjusted*
1.88 (1.36-2.61) 1.63 (1.18-2.27)
Unspecified IBD Age- and sex-adjusted Fully adjusted*
2.61 (1.09-6.30) 2.07 (0.86-5.00)
<0.0001 0.0002
0.0001 0.0033
M AN U
SC
Crohn's disease Age- and sex-adjusted Fully adjusted*
p-value
RI PT
HR (95% CI)
0.0320 0.1052
CI, confidence interval; HR, hazard ratio *Adjusted for age, sex, socioeconomic status, smoking, alcohol abuse, and healthcare consumption
EP AC C
347
TE D
346
Page 20 of 21
ACCEPTED MANUSCRIPT 348
Figure 1 – Baseline prevalence of inflammatory bowel disease among patients with hidradenitis
349
suppurativa and the general population
350
AC C
EP
TE D
M AN U
SC
RI PT
351
Page 21 of 21
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S0022-202X(17)30011-8
DOI:
10.1016/j.jid.2016.11.040
Reference:
JID 685
To appear in:
The Journal of Investigative Dermatology
Received Date: 17 October 2016 Revised Date:
11 November 2016
Accepted Date: 28 November 2016
Please cite this article as: Egeberg A, Jemec GBE, Kimball AB, Bachelez H, Gislason GH, Thyssen JP, Mallbris L, Prevalence and risk of inflammatory bowel disease in patients with hidradenitis suppurativa, The Journal of Investigative Dermatology (2017), doi: 10.1016/j.jid.2016.11.040. 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
Title Page
2
Title
3
Prevalence and risk of inflammatory bowel disease in patients with hidradenitis suppurativa
4
Manuscript word, table and figure count
5
2352 words, 4 tables, 1 figure
6
Authors full names, departments, and institutions
7
Alexander Egeberg1 MD, PhD; Gregor B.E. Jemec2 MD, DMSc; Alexa B. Kimball3 MD MPH; Hervé
8
Bachelez4 MD; Gunnar H. Gislason5,6,7 MD, PhD; Jacob P. Thyssen1 MD, PhD, DMSc; Lotus Mallbris8 MD,
9
PhD
M AN U
SC
RI PT
1
1) Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen,
11
Hellerup, Denmark
12
2) Department of Dermatology, Zealand University Hospital, Roskilde; University of Copenhagen, Denmark
13
3) Department of Dermatology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston,
14
Massachusetts, United States
15
4) Department of Dermatology, AP-HP Hôpital Saint-Louis; Sorbonne Paris Cité Université Paris Diderot;
16
INSERM U1163, Imagine Institute, Necker Hospital, Paris, France
17
5) Department of Cardiology, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
18
6) The Danish Heart Foundation, Copenhagen, Denmark
19
7) The National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark
20
8) Eli Lilly and Company, Indianapolis, Indiana, United States
21
Corresponding author
AC C
EP
TE D
10
Page 1 of 21
ACCEPTED MANUSCRIPT Alexander Egeberg, Department of Dermatology and Allergy, Herlev and Gentofte Hospital, Kildegårdsvej
23
28, 2900 Hellerup, Denmark
24
Telephone:
(0045) 24215421
25
E-mail:
[email protected]
RI PT
22
AC C
EP
TE D
M AN U
SC
26
Page 2 of 21
Abbreviations
28
CD
Crohn’s disease
29
HR
Hazard ratio
30
IBD
Inflammatory bowel disease
31
ICD
International Classification of Diseases
32
IL
Interleukin
33
OR
Odds ratio
34
SD
Standard deviation
35
TNF
Tumor necrosis factor
36
UC
Ulcerative colitis
M AN U
SC
27
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
37
Page 3 of 21
ACCEPTED MANUSCRIPT
Abstract
39
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease. In small studies, inflammatory bowel
40
disease (IBD) has been associated with increased prevalence of HS, but data on the concurrence of IBD in
41
patients with HS is limited. We therefore investigated the prevalence and risk of IBD in patients with HS
42
compared with the general population. The study linked all Danish individuals ≥18 years in nationwide
43
registers. Adjusted odds ratios (OR) and adjusted hazard ratios (HRs) were estimated by logistic regression
44
and Cox regression, respectively. The study comprised 7,732 patients with HS, and 4,354,137 subjects from
45
the general population. The prevalence (HS vs. general population) was 0.8% and 0.3% (OR 2.04; 1.59-2.62)
46
for CD and 1.3% and 0.7% (OR 1.75; 1.44-2.13) for UC. The risk of new-onset CD (HR 2.19; 1.44-3.34)
47
and UC (HR 1.63; 1.18-2.27) was significantly increased among patients with HS. In conclusion, HS was
48
significantly associated with presence and risk of new-onset IBD, although the prevalence remained low.
49
Gastrointestinal complaints in patients with HS should warrant further clinical examination.
M AN U
SC
RI PT
38
AC C
EP
TE D
50
Page 4 of 21
ACCEPTED MANUSCRIPT
Introduction
52
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease, characterized by painful recurrent,
53
suppurating and malodorous abscesses in areas rich with apocrine sweat glands, such as the axillae and
54
genital area.(Jemec, 2012) European studies have suggested a HS prevalence of 1-4% with a 3:1 female
55
preponderance, and the disease usually develops in subjects in their early twenties.(Jemec, 2012) The
56
psychosocial burden and negative impact of HS on quality of life is greater than that of other dermatological
57
conditions and the disease is likely to be both under-diagnosed and frequently associated with a 5-10 year-
58
long diagnostic delay.(Dufour et al., 2014, Jemec, 2012, Onderdijk et al., 2013, von der Werth and Jemec,
59
2001, Wolkenstein et al., 2007) Although the etiopathogenesis of HS is not fully understood, studies have
60
suggested the combination of a dysregulation of pilosebaceous unit homeostasis with cysts formation, and
61
dysregulated immune responses leading to chronic inflammation, with an assumed contribution of the
62
bacterial environment..(Kelly et al., 2015, Micheletti, 2014, Schlapbach et al., 2011, van der Zee et al., 2011)
63
Indeed, increased expression of inflammatory cytokines such as interleukin (IL)-1β, IL-10, IL-17, and tumor
64
necrosis factor (TNF)-α has been demonstrated in HS lesions and reports of elevated circulating levels of
65
TNF-α are suggestive of systemic inflammatory activation.(Kellyet al., 2015, Matusiak et al., 2009,
66
Schlapbachet al., 2011, van der Zeeet al., 2011) Indeed, a study of 50 Danish outpatient hospital patients
67
with HS and 250 matched controls from the same dermatology clinic found that patients with HS carry a
68
higher systemic inflammatory load, with higher circulating leukocyte counts and C-reactive protein levels
69
than, e.g., patients with psoriasis.(Riis et al., 2015)
70
Crohn’s disease (CD) and ulcerative colitis (UC) are the two predominant types of chronic relapsing
71
inflammatory disorders of the gastrointestinal tract, collectively referred to as inflammatory bowel disease
72
(IBD).(Abraham and Cho, 2009) Although CD and UC are immunologically and demographically different,
73
the two conditions can sometimes be hard to distinguish in early presentation. Dysregulation of the
74
gastrointestinal immune system in genetically predisposed individuals is believed to play an important part in
75
the pathogenesis of IBD.(Abraham and Cho, 2009) Interestingly, HS and IBD share numerous similarities
AC C
EP
TE D
M AN U
SC
RI PT
51
Page 5 of 21
ACCEPTED MANUSCRIPT suggestive of a shared pathogenesis. For example, smoking has been shown to be a worsening factor in HS
77
as well as in IBD.(Nazary et al., 2011, Rosenfeld and Bressler, 2012) Moreover, both HS and CD are
78
characterized by scarring and sinus tract formation,(Baumgart and Sandborn, 2007, Jemec, 2012) and Th-17
79
cells, IL-23 and TNF appear to be involved in HS as well as IBD.(Duerr et al., 2006, Schlapbachet al., 2011)
80
Along this line, certain genes e.g. SULT1B1 and SULT1E1 have been associated with HS as well as
81
IBD.(Janse et al., 2016)
82
While studies have suggested a link between HS and IBD, results are inconsistent and the association
83
remains poorly understood.(Principi et al., 2016, Shalom et al., 2016, van der Zee et al., 2014, van der Zee et
84
al., 2010, Yadav et al., 2016) We therefore examined the prevalence, co-occurrence, and risk of new-onset
85
IBD in patients with HS, using a nationwide cohort of the Danish population.
M AN U
SC
RI PT
76
86
Results
88
The study cohort comprised a total of 7,732 patients with a hospital (inpatient or ambulatory) diagnosis of
89
HS, and 4,354,137 general population control subjects. A strong female predominance (73.6%) was observed
90
among patients with HS, and smoking was significantly more frequent compared with the reference
91
population (p<0.0001). At baseline, the period prevalence (from 1978 until 2008) of CD was 0.3% and 0.8%
92
(Table 1, and Figure 1) in the reference population and in patients with HS, respectively, yielding an adjusted
93
OR of 2.04 (1.59-2.62; risk difference 0.003) (Table 2). Similarly, the prevalence of UC was 0.7% and 1.3%,
94
respectively, with an adjusted OR of 1.75 (1.44-2.13; risk difference 0.002). For patients with co-occurring
95
diagnosis of CD and UC (‘unspecified IBD’), the prevalence was 0.1% and 0.7%, respectively (adjusted OR
96
3.40; 2.60-4.44; risk difference 0.007). In cases where IBD preceded the onset of HS, the mean time from
97
IBD to HS was 8.5 (SD 7.3) years, whereas the mean time from HS to IBD was 9.7 (SD 7.9) years when HS
98
occurred first. During follow-up, a total of 4,001 and 22 patients developed new-onset CD, among the
99
reference population and patients with HS, respectively. Similarly, there were 10,359 and 36 cases of UC,
100
and 1,016 and 5 cases of unspecified IBD, respectively, during follow-up (Table 3). After adjustment for
AC C
EP
TE D
87
Page 6 of 21
ACCEPTED MANUSCRIPT potential confounding factors, the fully adjusted HR associated with HS was 2.19 (1.44-3.34) for CD, 1.63
102
(1.18-2.27) for UC, and 2.07 (0.86-5.00; p=0.1052 for unspecified IBD (Table 4). In sensitivity analyses,
103
additional adjustment of use of tetracycline class agents did not significantly alter any of the results
104
compared with our primary analyses (data not shown).
105
Discussion
106
In this nationwide study of the Danish population, we found that HS was associated with a significantly
107
increased risk of co-occurring and new-onset IBD, with a prevalence ranging from 0.7% to 1.3%, and an
108
incidence of 0.13 to 0.97 per 1,000 HS-patients per year.
109
Previous studies have reported vast discrepancies on the co-occurrence of HS and IBD. For example, in a
110
Dutch study,(Yadavet al., 2016) the prevalence of HS was 23% (n=223/1093) in a cohort of patients with
111
IBD, with higher prevalence for CD than UC.(van der Zeeet al., 2014) On the other hand, a population-based
112
study from Minnesota found a HS point prevalence of 1.2% (n=8/679) among patients with IBD, with an
113
incidence rate ratio of 8.9 (95% CI 3.6-17.5). While the majority of studies have examined the concurrence
114
of HS in IBD populations, one Israeli cross-sectional study (Shalomet al., 2016) of 3,207 patients with HS,
115
and 6,412 age- and sex-matched healthy control subjects reported an increased prevalence and risk of CD
116
(0.8% vs. 0.4%; adjusted OR 2.03; 95% CI 1.14-3.62) and UC (0.4% vs. 0.2%; adjusted OR 1.82; 95% CI
117
0.81-4.05), albeit that the latter did not reach statistical significance. Nevertheless, the adjusted estimates
118
appear to be in line with the findings from our cohort. Moreover, one very recent study from the Netherlands
119
found a 2.5% and 0.8% prevalence of CD and UC, respectively, among patients with HS.(Deckers et al.,
120
2016) To our knowledge, the present cohort is the largest study of prevalence and risk of IBD in patients
121
with pre-existing HS, and the findings expands the existing literature considerably by suggesting an
122
augmented prevalence and risk of new-onset IBD in patients with HS.
123
Several hypotheses have been put forward to potentially explain the link between HS and IBD. For example,
124
chronic gastrointestinal inflammation in IBD may result from abnormal immune responses to gut
125
microorganisms in genetically susceptible individuals.(Maloy and Powrie, 2011) Moreover, smoking plays
AC C
EP
TE D
M AN U
SC
RI PT
101
Page 7 of 21
ACCEPTED MANUSCRIPT an important role in HS as well as IBD.(Nazaryet al., 2011, Rosenfeld and Bressler, 2012) A history of
127
smoking was higher among patients with HS in our cohort, and while smoking may aggravate CD, it appears
128
to have beneficial effects on UC.(van der Heide et al., 2009) Shared genetic risk loci may also play a
129
role,(Janseet al., 2016, van der Zee et al., 2016) and while pro-inflammatory cytokines are upregulated in
130
HS,(Schlapbachet al., 2011) treatment with anti-TNF agents have shown promise in management of
131
HS.(Kimball et al., 2016). Finally, an increased prevalence of spondylarthropathy has been reported in
132
patients with IBD as well as in those with HS, raising the hypothesis that genetic, epigenetic and/or
133
environmental factors cooperate to lead to dysregulated inflammatory pathways across these immune-
134
mediated diseases.(Gionchetti et al., 2015, Richette et al., 2014)
135
Certain limitations apply to the interpretation of the present study. Due to the observational nature of our
136
study we cannot determine causality. We were unable to distinguish between severities of HS, and
137
while patients with HS in our study were identified by hospital diagnosis, studies have suggested
138
that patients with HS seen in hospital settings have more comorbidity than HS patients sampled
139
from a population setting.(Tzellos et al., 2015) Furthermore, although our endpoint was previously
140
validated, it has been suggested that HS may be misdiagnosed as cutaneous CD,(van der Zeeet al.,
141
2016) and we cannot refute that some misclassification could have occurred in this regard. Also,
142
while dichotomous proxy data on smoking and alcohol abuse were available, the lack of
143
quantitative data on (e.g. number of cigarettes or grams of alcohol per day) could have biased our
144
estimates. Lastly, the Danish population is predominantly of Northern European descent, and
145
extrapolation of results to patients with other ethnicities should be carried out with caution.
146
In conclusion, we found an increased prevalence and risk of new-onset CD and UC in patients with HS. The
147
link may be due to a shared immuno-pathogenesis, as well as modifiable life-style factors. In HS patients
148
presenting with gastrointestinal complaints, timely referral for gastroenterological evaluation of IBD may be
149
appropriate.
AC C
EP
TE D
M AN U
SC
RI PT
126
Page 8 of 21
ACCEPTED MANUSCRIPT
Materials and methods
151
Data sources and study population
152
Study approval was obtained from the Danish Data Protection Agency (ref. 2007-58-0015, int. ref. GEH-
153
2014-018, I-Suite 02736), and approval from an ethics committee is not required for registry studies in
154
Denmark. The study was conducted in accordance with the Strengthening the Reporting of Observational
155
Studies in Epidemiology recommendations.(von Elm et al., 2007)
156
Using the unique personal identification number assigned to all Danish citizens, we linked individual-level-
157
information from nationwide administrative registers. The Civil Registration System(Schmidt et al., 2014)
158
contains information on sex, date of birth, and updated information on vital status and emigration, thus
159
minimizing loss to follow-up. All in- and outpatient (ambulatory) hospital consultations are recorded in the
160
Danish National Patient Register(Andersen et al., 1999) (DNPR) including 1 primary and up to 19 secondary
161
diagnoses coded by discharging physicians according to the International Classification of Diseases, eighth
162
revision (ICD-8) (prior to 1994), and according to the tenth revision (ICD-10) thereafter. The primary
163
diagnosis is the main reason for the hospital consultation or hospitalization, and secondary diagnoses are
164
additional conditions, including complications. Since 1994, detailed and accurate information on all
165
pharmacy-dispensed medications has been registered in the Danish Registry of Medicinal Products
166
Statistics.(Gaist et al., 1997) Information on tax-reported household income is recorded by Statistics
167
Denmark.(Baadsgaard and Quitzau, 2011)
SC
M AN U
TE D
EP
AC C
168
RI PT
150
169
We identified all Danish adults (≥18 years) alive and resident in Denmark on January 1st 2008 (i.e. date of
170
study start for all individuals in the cohort). Subjects were followed from study start and until December 31st
171
2012, death, migration, or the occurrence of an endpoint, whichever came first. Patients were classified as
172
having HS if they prior to study start had received a diagnosis (inpatient or ambulatory) of HS (ICD-8 705.91
173
and ICD-10 L73.2) recorded in the DNPR. Collection of data on diabetes, hypertension, smoking history,
174
and alcohol abuse has been described elsewhere.(Egeberg et al., 2016a, Egeberg et al., 2016b, Olesen et al.,
Page 9 of 21
ACCEPTED MANUSCRIPT 2011) From Statistics Denmark we used information on tax-reported household income to calculate an age-
176
standardized index of socioeconomic status based on the mean gross annual income during a 5-year period
177
before study start.
178
Patients with IBD were defined as both hospitalized patients and patients in outpatient clinical settings who
179
had a recorded diagnosis of CD (ICD-8 codes 563.00–563.09 or ICD-10 code group K50) or UC (ICD-8
180
codes 563.19 or 569.04, or ICD-10 code group K51). Patients with concurrent diagnoses of both CD and UC
181
were characterized as having “unspecified IBD”, as these conditions may be subject to diagnostic overlap.
182
The completeness of IBD diagnoses from the DNPR was previously evaluated to be 94%, by comparing a
183
pathology database as reference, whereas the validity was 97% for CD and 90% for UC.(Fonager et al.,
184
1996)
M AN U
SC
RI PT
175
185 Statistical analysis
187
We described baseline characteristics with means and standard deviations for continuous variables and
188
frequencies and percentages for categorical variables. The baseline prevalence of IBD was determined as the
189
percentage of individuals which had received a diagnosis of CD or UC between January 1st 1978 (when the
190
DNPR was established) and January 1st 2008 (the study start date). SAS statistical software version 9.4 (SAS
191
Institute Inc. Cary, NC, USA) and STATA software version 13.0 (StataCorp, College Station, TX, USA)
192
were used to summarize incidence rates per 1,000 person-years, and Cox regression models were performed
193
to obtain hazard ratios (HRs) for the risk of incident IBD, whereas odds ratios (ORs) were calculated based
194
on logistic regression. Incidence of IBD during follow-up was calculated for all individuals without a history
195
of IBD prior to study start. HRs for IBD were calculated as age- and sex-adjusted, and fully adjusted (in
196
which age, sex, socioeconomic status, smoking, alcohol abuse, and healthcare consumption [number of clinic
197
visits] were considered). Since studies have suggested that tetracycline class agents, i.e. drugs frequently
198
used in treatment of HS, may influence the onset of IBD,(Margolis et al., 2010) we performed sensitivity
199
analyses adjusted for use of such drugs. Model assumptions were tested and found to be valid unless
AC C
EP
TE D
186
Page 10 of 21
ACCEPTED MANUSCRIPT otherwise specified. Two-tailed p-values less than 0.05 were considered statistically significant and results
201
were reported with 95% confidence intervals (CIs) where applicable.
202
Author Contributions
203
Drs. Egeberg and Gislason had full access to all of the data in the study and take responsibility for the
204
integrity of the data and the accuracy of the data analysis. Study concept and design: Egeberg. Acquisition,
205
analysis, and interpretation of data: All authors. Drafting of the manuscript: Egeberg. Critical revision of
206
the manuscript for important intellectual content: All authors. Statistical analysis: Egeberg and Gislason.
207
Obtained funding: Egeberg and Mallbris. Administrative, technical, or material support: Egeberg, Gislason,
208
and Thyssen. Study supervision: Egeberg and Gislason.
209
Declaration of interests
210
Dr. Egeberg has received research funding from Pfizer and Eli Lilly, and honoraria as consultant and/or
211
speaker from Pfizer, Eli Lilly, Novartis, Galderma, and Janssen Pharmaceuticals. Dr. Bachelez has received
212
consultancy and/or speaker honoraria from Abbvie, Amgen, Boehringer Ingelheim, Baxalta, Bayer, Celgene,
213
Janssen Pharmaceuticals, Leo Pharma, Eli Lilly, Novartis, Janssen-Cilag, Merck Sharp & Dohme, Pfizer,
214
Sandoz, Takeda, and grant support by Pfizer. Dr. Kimball received honoraria for serving as a consultant for
215
AbbVie, Dermira, Eli Lilly, Merck, Novartis, and Pfizer; received residency and fellowship program funding
216
from Janssen Pharmaceuticals; and received grant/research funding as an investigator for Abbott
217
Laboratories, Amgen, Dermira, Janssen, Merck, and Novartis. Dr. Gislason is supported by an unrestricted
218
research scholarship from the Novo Nordisk Foundation. Dr. Jemec is a consultant and investigator for
219
AbbVie and Novartis, has received unrestricted grants from Leo Pharma, and sits on the Advisory Board of
220
AbbVie, Novartis, Janssen Pharmaceuticals and MSD; and investigator for Regeneron. Dr. Mallbris is
221
currently employed by Eli Lilly and Company.
222
Funding sources
223
Eli Lilly and Company
AC C
EP
TE D
M AN U
SC
RI PT
200
Page 11 of 21
ACCEPTED MANUSCRIPT Funding/Sponsor was involved?
225
Design and conduct of the study
Yes ___
No _X_
226
Collection, management, analysis and interpretation of data
Yes _X_
No __
227
Preparation, review, or approval of the manuscript
Yes _X_
No __
228
Decision to submit the manuscript for publication
Yes _X_
No __
229
The funding sources participated in interpretation of the final analyzed study results, but had no access to the
230
raw data, and did not participate in data collection, management, or analysis.
AC C
EP
TE D
M AN U
SC
RI PT
224
Page 12 of 21
ACCEPTED MANUSCRIPT 231
Reference list
232 Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med 2009;361(21):2066-78.
234
Andersen TF, Madsen M, Jorgensen J, Mellemkjoer L, Olsen JH. The Danish National Hospital Register. A
237 238 239 240
Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet 2007;369(9573):1641-57.
Baadsgaard M, Quitzau J. Danish registers on personal income and transfer payments. Scand J Public Health
SC
236
valuable source of data for modern health sciences. Dan Med Bull 1999;46(3):263-8.
2011;39(7 Suppl):103-5.
Deckers IE, Benhadou F, Koldijk MJ, Del Marmol V, Horvath B, Boer J, et al. Inflammatory bowel disease
M AN U
235
RI PT
233
241
is associated with hidradenitis suppurativa: Results from a multicenter cross-sectional study. Journal
242
of the American Academy of Dermatology 2016.
244 245
Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006;314(5804):1461-3.
TE D
243
Dufour DN, Emtestam L, Jemec GB. Hidradenitis suppurativa: a common and burdensome, yet underrecognised, inflammatory skin disease. Postgraduate medical journal 2014;90(1062):216-21; quiz
247
20.
249 250
Egeberg A, Gislason G, Hansen P. Risk of major adverse cardiovascular events and all-cause mortality in patients with hidradenitis suppurativa. JAMA dermatology 2016a;152(4):1-6.
AC C
248
EP
246
Egeberg A, Mallbris L, Gislason GH, Skov L, Hansen PR. Risk of Multiple Sclerosis in Patients with
251
Psoriasis: A Danish Nationwide Cohort Study. The Journal of investigative dermatology
252
2016b;136(1):93-8.
253
Fonager K, Sorensen HT, Rasmussen SN, Moller-Petersen J, Vyberg M. Assessment of the diagnoses of
254
Crohn's disease and ulcerative colitis in a Danish hospital information system. Scandinavian journal
255
of gastroenterology 1996;31(2):154-9.
256
Gaist D, Sorensen HT, Hallas J. The Danish prescription registries. Dan Med Bull 1997;44(4):445-8.
Page 13 of 21
ACCEPTED MANUSCRIPT 257 258 259
Gionchetti P, Calabrese C, Rizzello F. Inflammatory Bowel Diseases and Spondyloarthropathies. J Rheumatol Suppl 2015;93:21-3. Janse IC, Koldijk MJ, Spekhorst LM, Vila AV, Weersma RK, Dijkstra G, et al. Identification of Clinical and Genetic Parameters Associated with Hidradenitis Suppurativa in Inflammatory Bowel Disease.
261
Inflammatory bowel diseases 2016;22(1):106-13.
RI PT
260
262
Jemec GB. Clinical practice. Hidradenitis suppurativa. N Engl J Med 2012;366(2):158-64.
263
Kelly G, Hughes R, Mc Garry T, van den Born M, Adamzik K, Fitzgerald R, et al. Dysregulated cytokine
266 267 268 269
SC
265
expression in lesional and non-lesional skin in Hidradenitis suppurativa. Br J Dermatol 2015. Kimball AB, Okun MM, Williams DA, Gottlieb AB, Papp KA, Zouboulis CC, et al. Two Phase 3 Trials of Adalimumab for Hidradenitis Suppurativa. N Engl J Med 2016;375(5):422-34.
M AN U
264
Maloy KJ, Powrie F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 2011;474(7351):298-306.
Margolis DJ, Fanelli M, Hoffstad O, Lewis JD. Potential association between the oral tetracycline class of antimicrobials used to treat acne and inflammatory bowel disease. The American journal of
271
gastroenterology 2010;105(12):2610-6.
272
TE D
270
Matusiak L, Bieniek A, Szepietowski JC. Increased serum tumour necrosis factor-alpha in hidradenitis suppurativa patients: is there a basis for treatment with anti-tumour necrosis factor-alpha agents?
274
Acta dermato-venereologica 2009;89(6):601-3.
276 277 278 279
Micheletti RG. Hidradenitis suppurativa: current views on epidemiology, pathogenesis, and pathophysiology. Semin Cutan Med Surg 2014;33(3 Suppl):S48-50.
AC C
275
EP
273
Nazary M, van der Zee HH, Prens EP, Folkerts G, Boer J. Pathogenesis and pharmacotherapy of Hidradenitis suppurativa. Eur J Pharmacol 2011;672(1-3):1-8. Olesen JB, Lip GY, Hansen ML, Hansen PR, Tolstrup JS, Lindhardsen J, et al. Validation of risk
280
stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation:
281
nationwide cohort study. BMJ 2011;342:d124.
282 283
Onderdijk AJ, van der Zee HH, Esmann S, Lophaven S, Dufour DN, Jemec GB, et al. Depression in patients with hidradenitis suppurativa. J Eur Acad Dermatol Venereol 2013;27(4):473-8.
Page 14 of 21
ACCEPTED MANUSCRIPT 284
Principi M, Cassano N, Contaldo A, Iannone A, Losurdo G, Barone M, et al. Hydradenitis suppurativa and
285
inflammatory bowel disease: An unusual, but existing association. World J Gastroenterol
286
2016;22(20):4802-11.
287
Richette P, Molto A, Viguier M, Dawidowicz K, Hayem G, Nassif A, et al. Hidradenitis suppurativa associated with spondyloarthritis -- results from a multicenter national prospective study. The
289
Journal of rheumatology 2014;41(3):490-4.
292 293 294 295 296 297
inflammatory load than other dermatological patients. Arch Dermatol Res 2015.
SC
291
Riis PT, Soeby K, Saunte DM, Jemec GB. Patients with hidradenitis suppurativa carry a higher systemic
Rosenfeld G, Bressler B. The truth about cigarette smoking and the risk of inflammatory bowel disease. The American journal of gastroenterology 2012;107(9):1407-8.
M AN U
290
RI PT
288
Schlapbach C, Hanni T, Yawalkar N, Hunger RE. Expression of the IL-23/Th17 pathway in lesions of hidradenitis suppurativa. Journal of the American Academy of Dermatology 2011;65(4):790-8. Schmidt M, Pedersen L, Sorensen HT. The Danish Civil Registration System as a tool in epidemiology. Eur J Epidemiol 2014;29(8):541-9.
Shalom G, Freud T, Ben Yakov G, Khoury R, Dreiher J, Vardy DA, et al. Hidradenitis Suppurativa and
299
Inflammatory Bowel Disease: A Cross-Sectional Study of 3,207 Patients. The Journal of
300
investigative dermatology 2016;136(8):1716-8.
TE D
298
Tzellos T, Zouboulis CC, Gulliver W, Cohen AD, Wolkenstein P, Jemec GB. Cardiovascular disease risk
302
factors in patients with hidradenitis suppurativa: a systematic review and meta-analysis of
303
observational studies. Br J Dermatol 2015.
AC C
304
EP
301
van der Heide F, Dijkstra A, Weersma RK, Albersnagel FA, van der Logt EM, Faber KN, et al. Effects of
305
active and passive smoking on disease course of Crohn's disease and ulcerative colitis. Inflammatory
306
bowel diseases 2009;15(8):1199-207.
307
van der Zee HH, de Ruiter L, van den Broecke DG, Dik WA, Laman JD, Prens EP. Elevated levels of
308
tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-10 in hidradenitis suppurativa
309
skin: a rationale for targeting TNF-alpha and IL-1beta. Br J Dermatol 2011;164(6):1292-8.
Page 15 of 21
ACCEPTED MANUSCRIPT 310 311 312
van der Zee HH, de Winter K, van der Woude CJ, Prens EP. The prevalence of hidradenitis suppurativa in 1093 patients with inflammatory bowel disease. Br J Dermatol 2014;171(3):673-5. van der Zee HH, Horvath B, Jemec GB, Prens EP. The Association between Hidradenitis Suppurativa and Crohn's Disease: in Search of the Missing Pathogenic Link. The Journal of investigative
314
dermatology 2016;136(9):1747-8.
316 317 318
van der Zee HH, van der Woude CJ, Florencia EF, Prens EP. Hidradenitis suppurativa and inflammatory bowel disease: are they associated? Results of a pilot study. Br J Dermatol 2010;162(1):195-7. von der Werth JM, Jemec GB. Morbidity in patients with hidradenitis suppurativa. Br J Dermatol
SC
315
RI PT
313
2001;144(4):809-13.
von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP, et al. The Strengthening the
320
Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting
321
observational studies. Lancet 2007;370(9596):1453-7.
322
M AN U
319
Wolkenstein P, Loundou A, Barrau K, Auquier P, Revuz J, Quality of Life Group of the French Society of D. Quality of life impairment in hidradenitis suppurativa: a study of 61 cases. J Am Acad Dermatol
324
2007;56(4):621-3.
325
TE D
323
Yadav S, Singh S, Edakkanambeth Varayil J, Harmsen WS, Zinsmeister AR, Tremaine WJ, et al. Hidradenitis Suppurativa in Patients With Inflammatory Bowel Disease: A Population-Based Cohort
327
Study in Olmsted County, Minnesota. Clin Gastroenterol Hepatol 2016;14(1):65-70.
329
AC C
328
EP
326
Page 16 of 21
ACCEPTED MANUSCRIPT 330
Table 1 – Baseline characteristics of the study population Reference population Hidradenitis suppurativa (n=4,354,137) (n=7,732)
Smoking, n (%) Alcohol abuse, n (%) Diabetes, n (%) Hypertension, n (%)
5,687 (73.6) 2,045 (26.4)
621 (8.3) 1,673 (21.6) 2,127 (27.5) 1,901 (24.6) 1,410 (18.2)
SC
871,896 (20.0) 870,665 (20.0) 870,209 (20.0) 870,440 (20.0) 870,927 (20.0)
RI PT
45.8 (12.2) 9.6 (4.6-16.1)
2,210,356 (50.8) 2,143,781 (49.2)
350,870 (8.1) 60,801 (1.4) 157,662 (3.6) 527,777 (12.1)
1,724 (22.3) 201 (2.6) 532 (6.9) 942 (12.2)
12,667 (0.3) 29,843 (0.7) 6,427 (0.1)
63 (0.8) 103 (1.3) 55 (0.7)
TE D
Prevalent IBD at baseline, n (%) Crohn's disease Ulcerative colitis Unspecified IBD
48.7 (18.0) NA
M AN U
Age, mean (SD) Disease duration, median (IQR) Sex, n (%) Women Men Socioeconomic status, n (%) Lowest Below average Average Above average Highest
332
AC C
331
EP
IBD, inflammatory bowel disease; IQR, interquartile range; NA, not applicable; SD, standard deviation
Page 17 of 21
ACCEPTED MANUSCRIPT 333
Table 2 – Odds ratios for association between hidradenitis suppurativa and inflammatory bowel
334
disease at baseline (cross-sectional study design) Fully adjusted* OR 95% CI p-value
Crohn's disease
2.61
2.03-3.34
<0.0001
2.04 1.59-2.62 <0.0001
Ulcerative colitis
1.96
1.61-2.37
<0.0001
1.75 1.44-2.13 <0.0001
Unspecificed IBD
4.50
3.45-5.88
<0.0001
3.40 2.60-4.44 <0.0001
SC
RI PT
Hidradenitis suppurativa
Age- and sex-adjusted OR 95% CI p-value
M AN U
OR, Odds ratio; CI, confidence interval; IBD, inflammatory bowel disease *age, sex, socioeconomic status, healthcare consumption, smoking and alcohol abuse 335
336
337
AC C
EP
TE D
338
Page 18 of 21
ACCEPTED MANUSCRIPT 339
Table 3 – Summary of number of new events, follow-up time, and incidence rates of inflammatory
340
bowel disease per 1,000 person-years
New-onset ulcerative colitis Follow-up time, years Number of events Incidence rate/1,000 PY 95% CI
20,714,056 10,359 0.50 0.49-0.51
20,848,622 1,016 0.05 0.05-0.05
37,015 36 0.97 0.70-1.35
37,326 5 0.13 0.06-0.32
TE D
New-onset unspecified IBD Follow-up time, years Number of events Incidence rate/1,000 PY 95% CI
37,240 22 0.59 0.39-0.90
SC
20,812,454 4,001 0.19 0.19-0.19
M AN U
New-onset Crohn's disease Follow-up time, years Number of events Incidence rate/1,000 PY 95% CI
RI PT
Reference population Hidradenitis suppurativa
343
AC C
342
EP
CI, confidence interval; PY, person-years 341
Page 19 of 21
ACCEPTED MANUSCRIPT 344
Table 4 – Hazard ratios for risk of new-onset inflammatory bowel disease among patients with
345
hidradenitis suppurativa compared with the general population (cohort study design)
2.83 (1.86-4.30) 2.19 (1.44-3.34)
Ulcerative colitis Age- and sex-adjusted Fully adjusted*
1.88 (1.36-2.61) 1.63 (1.18-2.27)
Unspecified IBD Age- and sex-adjusted Fully adjusted*
2.61 (1.09-6.30) 2.07 (0.86-5.00)
<0.0001 0.0002
0.0001 0.0033
M AN U
SC
Crohn's disease Age- and sex-adjusted Fully adjusted*
p-value
RI PT
HR (95% CI)
0.0320 0.1052
CI, confidence interval; HR, hazard ratio *Adjusted for age, sex, socioeconomic status, smoking, alcohol abuse, and healthcare consumption
EP AC C
347
TE D
346
Page 20 of 21
ACCEPTED MANUSCRIPT 348
Figure 1 – Baseline prevalence of inflammatory bowel disease among patients with hidradenitis
349
suppurativa and the general population
350
AC C
EP
TE D
M AN U
SC
RI PT
351
Page 21 of 21
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT