Introduction
Psoriasis is a common chronic inflammatory skin disease characterized by T helper cell infiltrates, predominately with T helper type 1 and T helper type 17 cells, and expression of IL-17, IL-23, and TNF-α. Clinically, psoriasis is characterized by either widespread or localized sharply demarcated silvery, scaly, and erythematous plaques distributed symmetrically.
Epidemiological studies have established strong associations between psoriasis and Crohn disease (CD) and ulcerative colitis (UC), with increased risk of CD and UC in patients with psoriasis and vice versa (
Egeberg et al., 2016- Egeberg A.
- Mallbris L.
- Warren R.B.
- Bachelez H.
- Gislason G.H.
- Hansen P.R.
- et al.
Association between psoriasis and inflammatory bowel disease: a Danish nationwide cohort study.
,
Eppinga et al., 2017- Eppinga H.
- Poortinga S.
- Thio H.B.
- Nijsten T.E.C.
- Nuij V.
- van der Woude C.J.
- et al.
Prevalence and phenotype of concurrent psoriasis and inflammatory bowel disease.
). CD and UC represent the two forms of inflammatory bowel disease (IBD) and are believed to occur as a host response to intestinal microbes in genetically predisposed individuals (
). IBD typically occurs in individuals aged 15–30 years, although it may occur at any age (
). Indeed, not only do psoriasis and IBD share important genetic risk loci, they also have crucial overlaps in their inflammatory pathways (
Ellinghaus et al., 2012- Ellinghaus D.
- Ellinghaus E.
- Nair R.P.
- Stuart P.E.
- Esko T.
- Metspalu A.
- et al.
Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci.
,
).
In recent years, significant advances have been made in the understanding and treatment of both psoriasis and IBD, and shared inflammatory pathways have enabled simultaneous treatment of both diseases with biologics targeting TNF-α and IL-12/23. However, although biologics inhibiting the IL-17 pathway have been shown to be efficacious for treatment of psoriasis and psoriatic arthritis (PsA) (
Frieder et al., 2018- Frieder J.
- Kivelevitch D.
- Haugh I.
- Watson I.
- Menter A.
Anti-IL-23 and anti-IL-17 biologic agents for the treatment of immune-mediated inflammatory conditions.
), concerns have been raised regarding their potential for worsening existing IBD or perhaps even inducing first-time CD or UC (
Egeberg, 2016Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis.
,
Hueber et al., 2012- Hueber W.
- Sands B.E.
- Lewitzky S.
- Vandemeulebroecke M.
- Reinisch W.
- Higgins P.D.
- et al.
Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial.
,
Reich et al., 2017- Reich K.
- Leonardi C.
- Langley R.G.
- Warren R.B.
- Bachelez H.
- Romiti R.
- et al.
Inflammatory bowel disease among patients with psoriasis treated with ixekizumab: a presentation of adjudicated data from an integrated database of 7 randomized controlled and uncontrolled trials.
,
Targan et al., 2016- Targan S.R.
- Feagan B.
- Vermeire S.
- Panaccione R.
- Melmed G.Y.
- Landers C.
- et al.
A randomized, double-blind, placebo-controlled phase 2 study of brodalumab in patients with moderate-to-severe Crohn’s disease.
,
van de Kerkhof et al., 2016- van de Kerkhof P.C.
- Griffiths C.E.
- Reich K.
- Leonardi C.L.
- Blauvelt A.
- Tsai T.F.
- et al.
Secukinumab long-term safety experience: a pooled analysis of 10 phase II and III clinical studies in patients with moderate to severe plaque psoriasis.
).
Data on incidence rates (IRs) of CD and UC among psoriasis patients in clinical trials have been conflicting and are difficult to compare with IRs from observational studies, because patient characteristics and diagnostic methods often differ considerably. The aims of this nationwide study was to examine the incidence and risk of CD and UC in patients with psoriasis treated with topical, systemic nonbiologic, and biologic therapy and to provide strata-specific data on the IBD.
Discussion
In this nationwide cohort study spanning two decades, we found a significantly increased risk of CD and UC among patients with psoriasis. No differences were seen in anatomical IBD location between psoriasis patients and the general population. Higher CD (but not UC) risk was seen with longer psoriasis duration.
In line with our findings, a previous Danish study found a positive association between psoriasis and risk of CD and UC, although IBD was not limited to diagnoses made by gastroenterologists (
Egeberg et al., 2016- Egeberg A.
- Mallbris L.
- Warren R.B.
- Bachelez H.
- Gislason G.H.
- Hansen P.R.
- et al.
Association between psoriasis and inflammatory bowel disease: a Danish nationwide cohort study.
). Moreover, that study pooled together use of certain systemic nonbiologic and biologic therapies (i.e., retinoids, psoralens, etanercept, and ustekinumab) but did not assess the relationship with a number of other frequently used treatment modalities (including methotrexate, cyclosporine, apremilast, infliximab, adalimumab, and secukinumab). This study therefore expands the existing literature considerably, not only by using more rigorous criteria for IBD (definite/probable/possible) but also by showing specific risk estimates among patients receiving topical therapy (mild psoriasis), systemic nonbiologic therapy (moderate to severe psoriasis), biologic treatment (most severe psoriasis). However, only relatively few patients (n = 2,187) were treated with biologics, thereby limiting interpretation of IBD risk in these patients. Since their introduction, adalimumab and ustekinumab have been the most frequently used biologics for psoriasis in Denmark (
Egeberg et al., 2018a- Egeberg A.
- Ottosen M.B.
- Gniadecki R.
- Broesby-Olsen S.
- Dam T.N.
- Bryld L.E.
- et al.
Safety, efficacy and drug survival of biologics and biosimilars for moderate-to-severe plaque psoriasis.
), which may explain the lack of association with IBD in the biologics-treated cohort, because these drugs may also dampen symptoms of IBD. Consequently, patients receiving biologic treatment of their psoriasis would experience fewer IBD symptoms and would therefore be less likely to be diagnosed with IBD. On the other hand, because studies have reported that multiple sclerosis is less severe in patients with concomitant IBD (
Zephir et al., 2014- Zephir H.
- Gower-Rousseau C.
- Salleron J.
- Simon O.
- Debouverie M.
- Le Page E.
- et al.
Milder multiple sclerosis course in patients with concomitant inflammatory bowel disease.
), and it is tempting to speculate that milder psoriasis may indeed be more strongly associated with IBD as well. Indeed, one previous study reported that patients with psoriasis and concurrent IBD had a milder psoriasis phenotype compared with psoriasis patients without IBD, whereas patients with CD and concurrent psoriasis had more severe CD compared with patients without psoriasis (
Eppinga et al., 2017- Eppinga H.
- Poortinga S.
- Thio H.B.
- Nijsten T.E.C.
- Nuij V.
- van der Woude C.J.
- et al.
Prevalence and phenotype of concurrent psoriasis and inflammatory bowel disease.
). Along these lines, it is well-established that although psoriasis is slightly more frequent in women, women tend to have milder psoriasis than men (
Hagg et al., 2017- Hagg D.
- Sundstrom A.
- Eriksson M.
- Schmitt-Egenolf M.
Severity of psoriasis differs between men and women: a study of the clinical outcome measure Psoriasis Area and Severity Index (PASI) in 5438 Swedish Register patients.
). In our study, there were striking sex differences, for example, a noticeably higher incidence of CD among women with psoriasis (
Figure 2). Female sex is also a risk factor for complications such as colectomy among IBD patients (
Burisch et al., 2017- Burisch J.
- Ungaro R.
- Vind I.
- Prosberg M.V.
- Bendtsen F.
- Colombel J.F.
- et al.
Proximal disease extension in patients with limited ulcerative colitis: a Danish population-based inception cohort.
), and a very recent study found a lower CD risk in females than males in childhood but higher female risk after the age of 25 years (
Shah et al., 2018- Shah S.C.
- Khalili H.
- Gower-Rousseau C.
- Olen O.
- Benchimol E.I.
- Lynge E.
- et al.
Sex differences in inflammatory bowel disease incidence.
), highlighting the importance of these observed sex differences. Although psoriasis patients tend to smoke more than the general population, smoking may aggravate CD while having beneficial effects on UC (
van der Heide et al., 2009- van der Heide F.
- Dijkstra A.
- Weersma R.K.
- Albersnagel F.A.
- van der Logt E.M.
- Faber K.N.
- et al.
Effects of active and passive smoking on disease course of Crohn’s disease and ulcerative colitis.
). The high increased risk of CD and UC among psoriasis patients with concurrent PsA may, at least in part, be explained by shared genetic risk loci such as IL12B, 5q31, IL23R, and IL2/IL21 (
).
In their respective clinical development programs, the incidence of IBD among patients treated with IL-17 inhibitors has been conspicuously higher than what we observed in our psoriasis population. Between-study comparison of IRs may be challenging, because different diagnostic methods may be applied. For example, during the ixekizumab clinical trial program, adjudication was performed using the methodology applied in the well-established Registre Epidemiologique des Maladies de l’Appareil Digestif (EPIMAD) registry (
Gower-Rousseau et al., 1994- Gower-Rousseau C.
- Salomez J.L.
- Dupas J.L.
- Marti R.
- Nuttens M.C.
- Votte A.
- et al.
Incidence of inflammatory bowel disease in northern France (1988-1990).
), whereas identification of CD and UC in the secukinumab trials was “based on customized broad search criteria” (
van de Kerkhof et al., 2016- van de Kerkhof P.C.
- Griffiths C.E.
- Reich K.
- Leonardi C.L.
- Blauvelt A.
- Tsai T.F.
- et al.
Secukinumab long-term safety experience: a pooled analysis of 10 phase II and III clinical studies in patients with moderate to severe plaque psoriasis.
, pp 89). Nonetheless, from their clinical development programs, it was reported that IRs (shown here per 10,000 person-years) of CD were 11 (95% CI = 5–23) for ixekizumab (
Reich et al., 2017- Reich K.
- Leonardi C.
- Langley R.G.
- Warren R.B.
- Bachelez H.
- Romiti R.
- et al.
Inflammatory bowel disease among patients with psoriasis treated with ixekizumab: a presentation of adjudicated data from an integrated database of 7 randomized controlled and uncontrolled trials.
), 11 (95% CI = 2–32) for secukinumab (
van de Kerkhof et al., 2016- van de Kerkhof P.C.
- Griffiths C.E.
- Reich K.
- Leonardi C.L.
- Blauvelt A.
- Tsai T.F.
- et al.
Secukinumab long-term safety experience: a pooled analysis of 10 phase II and III clinical studies in patients with moderate to severe plaque psoriasis.
), and 20 (95% CI not reported) for brodalumab (
Lebwohl et al., 2015- Lebwohl M.
- Strober B.
- Menter A.
- Gordon K.
- Weglowska J.
- Puig L.
- et al.
Phase 3 studies comparing brodalumab with ustekinumab in psoriasis.
), with IRs of UC being 19 (95% CI = 11–23) for ixekizumab (
;
Reich et al., 2017- Reich K.
- Leonardi C.
- Langley R.G.
- Warren R.B.
- Bachelez H.
- Romiti R.
- et al.
Inflammatory bowel disease among patients with psoriasis treated with ixekizumab: a presentation of adjudicated data from an integrated database of 7 randomized controlled and uncontrolled trials.
) and 15 (95% CI = 4–38) for secukinumab (
van de Kerkhof et al., 2016- van de Kerkhof P.C.
- Griffiths C.E.
- Reich K.
- Leonardi C.L.
- Blauvelt A.
- Tsai T.F.
- et al.
Secukinumab long-term safety experience: a pooled analysis of 10 phase II and III clinical studies in patients with moderate to severe plaque psoriasis.
). However, although the incidence of CD and UC may be increased with use of antibodies targeting IL-17, the absolute risk associated with these drugs remains low. Although the exact reason for the increased risk remains unclear, inhibition of IL-17 has been shown to weaken the intestinal epithelial barrier, thereby leading to increased gastrointestinal inflammation (
Lee et al., 2015- Lee J.S.
- Tato C.M.
- Joyce-Shaikh B.
- Gulen M.F.
- Cayatte C.
- Chen Y.
- et al.
Interleukin-23-independent IL-17 production regulates intestinal epithelial permeability.
,
Maxwell et al., 2015- Maxwell J.R.
- Zhang Y.
- Brown W.A.
- Smith C.L.
- Byrne F.R.
- Fiorino M.
- et al.
Differential roles for interleukin-23 and interleukin-17 in intestinal immunoregulation.
). Although this study may help put these clinical trial data into context, we emphasize that this study was not aimed at assessing IBD risk associated with specific drugs.
Several strengths and limitations of this study warrant discussion. Exclusion of confirmed or suspected IBD before the study start enabled a more direct comparison with IRs observed in clinical trials, whereas the inclusion of probable IBD diagnoses enabled comparison with clinical trials in which potential IBD cases that cannot definitively be confirmed to be either CD or UC were included. Moreover, possible IBD may include patients with unspecific gastrointestinal symptoms that may constitute irritable bowel syndrome or other gastroenterological conditions that do not meet the formal diagnostic criteria of CD or UC and may be a more realistic representation of the gastrointestinal complaints that patients report, for example, when consulting a dermatologist. However, although we defined cases of definite CD and UC as patients for whom the diagnosis was ascertained by a gastroenterologist, we lacked information on the specific diagnostic criteria on which the diagnosis was based, including data such as endoscopy findings and gastrointestinal histology samples. Moreover, in the psoriasis clinical trial program for ixekizumab, adjudication was performed in accordance with the EPIMAD definition, whereas our IBD cases were not, and although our IRs may be more appropriate for direct comparison with those from clinical trials, these definitory differences should be kept in mind when interpreting our findings. Furthermore, description of family history of IBD was limited by the fact that information on true biological relatives is not always recorded, for example, in cases of adoption or migration. Finally, we had approximately 8,100 person-years of exposure to biologics during our study (of which 76.4 person-years were for secukinumab), which may limit interpretability of our findings in the biologics-treated group, and especially with regard to IBD risk in patients receiving anti-IL-17 therapy.
In conclusion, we found an increased risk of CD and UC in patients with psoriasis. Patients with concurrent PsA had the highest risk of CD but not UC. Female sex and PsA were noticeable risk factors for IBD. Patients receiving biologic therapy for psoriasis did not have an increased IBD risk compared with the general population, likely because many anti-psoriatic biologics (e.g., adalimumab, infliximab, and ustekinumab) are also effective in treating symptoms of IBD, thereby postponing time to diagnosis. Although timely referral may be appropriate in patients presenting with gastrointestinal complaints consistent with IBD, the absolute psoriasis-associated risk of CD and UC remains low.
Materials and Methods
Study approval was obtained from the Danish Data Protection Agency. Register studies do not require ethical approval in Denmark.
Data sources and study population
Routinely collected administrative and health care data in Denmark can be linked at the individual level for research purposes using the unique identification number assigned to all residents at birth or migration (
Schmidt et al., 2014- Schmidt M.
- Pedersen L.
- Sorensen H.T.
The Danish Civil Registration System as a tool in epidemiology.
). The tax-supported health care system provides unencumbered access to health care, including general practitioners and hospitals, for all Danish residents. All hospital admissions and outpatient consultations are recorded in the Danish National Patient Register according to the Danish modification of the ICD-10 (
Andersen et al., 1999- Andersen T.F.
- Madsen M.
- Jorgensen J.
- Mellemkjoer L.
- Olsen J.H.
The Danish National Hospital Register. A valuable source of data for modern health sciences.
). Drugs given during hospital admission, or dispensed from hospital clinics (e.g., biologic therapy) are also recorded in this register, whereas all prescriptions dispensed from pharmacies are registered in the Danish Registry of Medicinal Products Statistics (
). Primary care services, including general practitioner and private clinics, are recorded in the Danish National Health Service Register (
Andersen et al., 2011- Andersen J.S.
- Olivarius Nde F.
- Krasnik A.
The Danish National Health Service Register.
). Data on smoking and alcohol abuse were collected by data retrieval algorithms, as previously described (
). Information on tax-reported household income is recorded by Statistics Denmark (
), and information on age, sex, vital statistics, and migration status is available from the Civil Registration System (
Schmidt et al., 2014- Schmidt M.
- Pedersen L.
- Sorensen H.T.
The Danish Civil Registration System as a tool in epidemiology.
).
From a source population comprising all Danish adults (≥18 years) between January 1, 1997, and December 31, 2016, we identified all patients with recorded codes consistent with psoriasis, as previously described (
). The study start for patients was the date of first recorded occurrence of psoriasis or their 18th birthday, whichever came last. Patients were followed up until the first of either December 31, 2016; death; migration; or the occurrence of an endpoint. Patient were matched (birth date and sex) with general population individuals in a 1:1 ratio. The index date (study start date) for the matched individuals was the same as for the corresponding psoriasis patients. To ensure that we captured only new-onset IBD during follow-up, study subjects were excluded if they had received a diagnosis of either confirmed or suspected IBD any time before the index date. The Strengthening the Reporting of Observational Studies in Epidemiology recommendations were used for conduct and reporting of this study (
von Elm et al., 2007- von Elm E.
- Altman D.G.
- Egger M.
- Pocock S.J.
- Gotzsche P.C.
- Vandenbroucke J.P.
- et al.
The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.
).
Endpoints
The co-primary IBD endpoints were a first-time diagnosis of CD (ICD-10 K50) or UC (ICD-10 K51). The IBD diagnosis was categorized into definite IBD, probable IBD, and possible IBD. Definite IBD included only patients who received an IBD diagnosis (CD or UC) that was verified by a gastroenterologist and did not have any subsequent diagnosis of UC (for patients with definite CD) or CD (for patients with definite UC). Probable IBD included patients who received an IBD diagnosis either by a gastroenterologist, abdominal surgeon, or internal medicine specialist. Possible IBD included any physician diagnosis of IBD (confirmed or suspected), regardless of specialty.
Statistical analysis
Descriptive characteristics were presented as means and standard deviations for continuous variables and frequencies and as percentages for categorical variables. Patients were divided into groups and categorized according to their use of treatments prescribed specifically for treatment of their psoriasis and divided into the following groups: (i) topical or no treatment, (ii) systemic nonbiologic treatment, and (iii) biologic treatment. Topical treatment included topical corticosteroids and/or topical vitamin D analogs. Systemic nonbiologic treatment included methotrexate, cyclosporine, acitretin, and apremilast. Biologic treatment included adalimumab, etanercept, infliximab, ustekinumab, and secukinumab. To accurately assess the impact of psoriasis treatment, these drugs were included only if they were prescribed specifically for psoriasis. To ensure correct risk-time allocation and to explore the temporal relationship, such psoriasis therapy was included as a time-varying variable, whereby patients could contribute risk-time in the topical treatment group until they received their first systemic nonbiologic or biologic treatment (if appropriate). Similarly, patients were considered exposed in the systemic nonbiologic group only until they were switched to a biologic, at which time they would contribute risk-time in the biologics-treated group. We presented IRs per 10,000 person-years of exposure and calculated aHRs (in which age, sex, socioeconomic status, smoking, and alcohol abuse were considered) through Cox regression models. Socioeconomic status was calculated as an age-standardized index (quintiles) based on the mean annual household income in the last 5 years before the study start. IRs and HRs were presented overall and in strata based on presence or absence of PsA and in age bands. We performed sensitivity analyses with additional adjustment for use of nonsteroidal anti-inflammatory drugs, systemic antibiotics, and oral contraceptives. To ensure that our findings were not solely explained by differences in health care use, we also performed a sensitivity analysis in which the reference population was sampled from people without psoriasis who were seen in the Danish health care system within 30 days of the index date for the respective psoriasis patients. Model assumptions, including the absence of interactions between model covariates, were tested and found to be valid unless otherwise specified. All statistical tests were conducted using a level of significance of 0.05, and results were reported with 95% confidence intervals (CIs), where applicable. All analyses were performed using SAS statistical software, version 9.4 (SAS Institute, Cary, NC) and STATA software, version 13.0 (StataCorp, College Station, TX).
Conflict of Interest
Outside of the submitted work, AE has received research funding from Pfizer, Eli Lilly, the Danish National Psoriasis Foundation, and the Kgl Hofbundtmager Aage Bang Foundation and honoraria as a consultant and/or speaker from Almirall; Leo Pharma; Samsung Bioepis Co., Ltd.; Pfizer; Eli Lilly; Novartis; Galderma; and Janssen Pharmaceuticals. Outside of the submitted work, JPT is supported by an unrestricted grant from the Lundbeck Foundation and has received speaker honoraria from Galderma, Sanofi-Genzyme, LEO Pharma, and MEDA; has attended advisory board meetings for Roche, Eli Lilly, and Sanofi-Genzyme; and is an investigator for LEO Pharma and Eli Lilly. Outside of the submitted work, JB reports personal fees from AbbVie, Janssen-Cilag, Celgene, MSD, Pfizer, and Takeda and nonfinancial support from Calpro. Outside of the submitted work, J-FC has served as a consultant or advisory board member for Abbvie, Amgen, Boehringer-Ingelheim, Celgene Corporation, Celltrion, Enterome, Ferring, Genentech, Janssen and Janssen, Eli Lilly, Medimmune, Merck & Co., Pfizer, Protagonist, Second Genome, Seres, Shire, Takeda, and Theradiag; has been a speaker for Abbvie and Ferring; has been a member of the speaker’s bureau for Amgen; and has stock options with Intestinal Biotech Development and Genfit.
Article info
Publication history
Published online: August 18, 2018
Accepted:
July 25,
2018
Received in revised form:
July 24,
2018
Received:
May 27,
2018
accepted manuscript published online 18 August 2018; corrected proof published online 19 October 2018
Copyright
© 2018 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology.