Incidence and Risk of Inflammatory Bowel Disease in Patients with Psoriasis—A Nationwide 20-Year Cohort Study

Open ArchivePublished:August 18, 2018DOI:https://doi.org/10.1016/j.jid.2018.07.029
      In psoriasis patients, incidence rates of Crohn disease (CD) and ulcerative colitis (UC) have been increased in epidemiological studies and certain clinical trials, yet the association remains poorly understood. We studied a 20-year nationwide cohort of 235,038 Danish adults with psoriasis and a 1:1 matched reference group. Less than 1% of psoriasis patients developed CD or UC during follow-up. Incidence rates of CD were highest for younger women with psoriasis and patients with concurrent psoriatic arthritis, whereas men with psoriasis had particularly high incidence rates of UC compared with their non-psoriasis peers. Adjusted hazard ratios of CD were 1.84 (95% confidence interval [CI]= 1.47–2.29) and 2.38 (95% CI = 1.62–3.49) among psoriasis patients treated with topical and systemic nonbiologic therapy, respectively. No definite CD cases occurred during biologic therapy. For UC, adjusted hazard ratios were 1.49 (95% CI = 1.29–1.72), 1.51 (95% CI = 1.14–2.01), and 1.23 (95% CI = 0.39–3.86, P = 0.7197) for psoriasis patients receiving topical, systemic nonbiologic, and biologic therapy, respectively. Time to CD (but not UC) diagnosis was significantly longer for psoriasis patients compared with the general population, and patients receiving systemic treatment had the longest time to CD and UC. Psoriasis was associated with increased risk of CD and UC. Particular risk factors included sex and psoriatic arthritis.

      Abbreviations:

      aHR (adjusted hazard ratio), CD (Crohn disease), CI (confidence interval), IBD (inflammatory bowel disease), ICD-10 (International Classification of Diseases, 10th revision), IR (incidence rate), PsA (psoriatic arthritis), UC (ulcerative colitis)

      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 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 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 (
      • Abraham C.
      • Cho J.H.
      Inflammatory bowel disease.
      ). IBD typically occurs in individuals aged 15–30 years, although it may occur at any age (
      • Loftus Jr., E.V.
      • Sandborn W.J.
      Epidemiology of inflammatory bowel disease.
      ). Indeed, not only do psoriasis and IBD share important genetic risk loci, they also have crucial overlaps in their inflammatory pathways (
      • Ellinghaus D.
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      • 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.
      ,
      • Fiorino G.
      • Omodei P.D.
      Psoriasis and inflammatory bowel disease: two sides of the same coin?.
      ).
      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 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 A.
      Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis.
      ,
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      • 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 K.
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      • 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.
      ,
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      • 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.
      ,
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      • 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.

      Results

      The study cohort comprised a total of 235,038 patients with psoriasis and 235,038 matched non-psoriasis individuals from the general population, all without a history of CD or UC at baseline. Among patients receiving topical treatment or systemic nonbiologic therapy and the general population, there was a slight female predominance, whereas the majority of biologics-treated patients were men (Table 1). The mean age at baseline was lower among patients who received treatment with biologics during the study compared with psoriasis patients receiving topical or systemic nonbiologic therapy. A positive family history (in a first-degree relative) of IBD was slightly more frequent among patients with psoriasis, with comparable estimates among those patients receiving topical, systemic nonbiologic, and biologic therapy. Patients with psoriasis had a higher prevalence of smoking, alcohol abuse, and medical comorbidity compared with the general population (Table 1).
      Table 1Characteristics of the the study population
      CharacteristicGeneral PopulationPsoriasis
      TopicalSystemic NonbiologicBiologic
      Number235,038209,36723,4842,187
      Age, years
       Mean (SD)51.0 (18.6)50.1 (18.9)52.5 (16.0)37.5 (13.2)
       Median (IQR)52.2 (36.6–65.1)52.5 (36.1–65.3)53.8 (41.5–64.1)37.5 (27.0–47.0)
      Sex, n (%)
       Women124,342 (52.9)110,852 (53.0)12,729 (54.2)761 (34.8)
       Men110,696 (47.1)98,515 (47.1)10,755 (45.8)1,426 (65.2)
      Available data on family history, n (%)135,688 (57.7)122,564 (58.5)12,243 (52.1)1,773 (81.1)
       First-degree relative with IBD3,845 (2.8)4,023 (3.3)387 (3.2)57 (3.2)
      Smoking, n (%)33,087 (14.1)38,158 (18.2)5,596 (23.8)403 (18.4)
      Alcohol abuse, n (%)15,496 (6.6)17,506 (8.4)2,098 (8.9)244 (10.2)
      Education level, n (%)
       Primary school78,286 (33.3)71,913 (34.4)8,716 (37.1)772 (35.3)
       Middle school14,807 (6.3)13,181 (6.3)896 (3.8)165 (7.5)
       High school and vocational school78,234 (33.3)71,147 (34.0)9,108 (38.8)807 (36.9)
       Short higher education30,136 (12.8)25,813 (12.3)2,621 (11.2)210 (9.6)
       Bachelor’s degree3,017 (1.3)2,448 (1.2)135 (0.6)24 (1.1)
       Master’s degree13,423 (5.7)10,741 (5.1)676 (2.9)76 (3.5)
       Doctorate degree and research fellowships716 (0.3)474 (0.2)32 (0.1)4 (0.2)
       Other/unregistered16,419 (7.0)13,650 (6.5)1,300 (5.5)129 (5.9)
      Income level, n (%)
       Lowest48,735 (20.7)42,528 (20.3)3,358 (14.3)517 (23.6)
       Below average45,353 (19.3)42,384 (20.2)4,903 (20.9)289 (13.2)
       Average45,660 (19.4)42,044 (20.1)5,497 (23.4)498 (22.8)
       Above average27,253 (20.1)40,919 (19.5)5,480 (23.3)515 (23.6)
       Highest48,037 (20.4)21,492 (19.8)4,246 (18.1)368 (16.8)
      Comorbidity, n (%)
       Diabetes, at baseline12,489 (5.3)14,774 (7.1)1,565 (6.7)50 (2.3)
       Diabetes, during follow-up20,939 (8.9)24,533 (11.7)3,381 (14.4)263 (12.0)
       Hypertension, at baseline30,067 (14.1)36,492 (17.4)3,820 (16.3)111 (5.1)
       Hypertension, during follow-up49,479 (21.1)51,647 (24.7)7,051 (30.0)443 (20.3)
       Statin use, at baseline
      1 Prescription within past 6 months.
      1,819 (0.8)1,871 (0.9)269 (1.2)10 (0.5)
       Statin use, during follow-up53,204 (22.6)54,833 (26.2)7,750 (33.0)543 (24.8)
       Psoriatic arthritis, at baseline0 (0.0)3,134 (1.5)2,146 (9.1)188 (8.6)
       Psoriatic arthritis, during follow-up0 (0.0)6,807 (3.3)5,329 (22.7)936 (42.8)
      Abbreviations: IBD, inflammatory bowel disease; IQR, interquartile range; SD, standard deviation.
      1 Prescription within past 6 months.

       Crohn disease

      During the study period, a total of 257/464/664 and 124/252/383 cases of definite/probable/possible CD occurred among patients with psoriasis and the general population, respectively (Figure 1 and Table 2). The IR (per 10,000 person-years) of definite CD was 1.55 (95% confidence interval [CI] = 1.37–1.76) among patients with psoriasis and 0.79 (95% CI = 0.67–0.95) in the age- and sex-matched general population. Stratified by psoriasis treatment, the IRs of definite CD were 1.96 (95% CI = 1.40–2.75) among those receiving systemic nonbiologic therapy and 1.51 (95% CI = 1.32–1.73) among patients receiving topical treatment. The IRs of definite/probable/possible CD among psoriasis patients with and without concurrent PsA are presented in Supplementary Table S1 online. Incidence of CD decreased with increasing age (see Supplementary Table S2 online). After adjustment for potential confounding factors, psoriasis was significantly associated with increased risk of definite CD (adjusted hazard ratio [aHR] = 1.88, 95% CI = 1.51–2.34), probable CD (aHR = 1.74, 95% CI = 1.49–2.03), and possible CD (aHR = 1.63, 95% CI = 1.44–1.85), respectively. Although the risk of CD was increased in patients receiving topical and systemic nonbiologic treatment, the aHR of CD was not significantly increased in patients treated with biologic therapy, regardless of presence or absence of PsA (Table 3), although the sample size of patients treated with biologics was much smaller than the other treatment modalities. Limiting analyses of PsA to patients for whom the diagnosis had been verified by a rheumatologist, the aHR of CD was 2.90 (95% CI = 1.61–5.22).
      Figure thumbnail gr1
      Figure 1Prevalence of inflammatory bowel disease (IBD) in patients with psoriasis. Percentage of patients developing new-onset Crohn disease (CD) and ulcerative colitis (UC) during follow-up.
      Table 2Summary of number of events, follow-up time, and incidence rates per 10,000 person-years
      DiagnosisGeneral PopulationPsoriasis
      Any PsoriasisTopicalSystemic NonbiologicBiologic
      Definite Crohn disease
       Follow-up time, years1,560,8731,591,6801,410,185173,3178,178
       Number of events124247213340
       IR per 10,000 person-years (95% CI)0.79 (0.67–0.95)1.55 (1.37–1.76)1.51 (1.32–1.73)1.96 (1.40–2.75)Not applicable
      Probable Crohn disease
       Follow-up time, years1,560,6211,590,5731,409,244173,1738,156
       Number of events25246440855<3
       IR per 10,000 person-years (95% CI)1.62 (1.43–1.83)2.92 (2.66–3.20)2.90 (2.62–3.19)3.18 (2.44–4.14)1.23 (0.17–8.70)
      Possible Crohn disease
       Follow-up time, years1,559,7161,589,6531,408,477173,0398,136
       Number of events383664583783
       IR per 10,000 person-years (95% CI)2.46 (2.22–2.71)4.18 (3.87–4.51)4.14 (3.81–4.49)4.51 (3.61–5.63)3.69 (1.19–11.43)
      Definite ulcerative colitis
       Follow-up time, years1,560,1701,590,7331,409,388173,1878,158
       Number of events325504444573
       IR per 10,000 person-years (95% CI)2.08 (1.87–2.32)3.17 (2.90–3.46)3.15 (2.87–3.45)3.29 (2.54–4.27)3.68 (1.19–11.40)
      Probable ulcerative colitis
       Follow-up time, years1,558,8991,588,5251,407,505172,8878,183
       Number of events546870768966
       IR per 10,000 person-years (95% CI)3.50 (3.22–3.81)5.48 (5.12–5.85)5.46 (5.08–5.86)5.55 (4.55–6.78)7.48 (3.31–16.42)
      Possible ulcerative colitis
       Follow-up time, years1,557,7351,586,3431,405,698172,5218,123
       Number of events7781,2741,1231465
       IR per 10,000 person-years (95% CI)4.99 (4.66–5.36)8.03 (7.60–8.48)7.99 (7.54–8.47)8.46 (7.20–9.96)6.16 (2.56–14.79)
      Due to data security requirements, data on one or two events are shown as <3.
      Abbreviations: CI, confidence interval; IR, incidence rate.
      Table 3HRs of the risk of Crohn disease in patients with psoriasis compared with the general population
      Psoriasis TypeDefinite CDProbable CDPossible CD
      Adjusted HR95% CIP-ValueAdjusted HR95% CIP-ValueAdjusted HR95% CIP-Value
      Any psoriasis1.881.512.34<0.00011.741.492.03<0.00011.631.441.85<0.0001
       Topical treatment1.841.47–2.29<0.00011.721.47–2.02<0.00011.621.42–1.84<0.0001
       Systemic nonbiologic treatment2.381.62–3.49<0.00011.921.43–2.58<0.00011.741.36–2.23<0.0001
       Biologic treatmentNot applicable0.560.08–4.000.56221.200.38–3.750.7561
      Psoriasis without PsA1.831.472.27<0.00011.701.461.99<0.00011.591.401.81<0.0001
       Topical treatment1.811.45–2.27<0.00011.701.45–2.00<0.00011.591.39–1.81<0.0001
       Systemic nonbiologic treatment2.081.34–3.23<0.00011.761.26–2.450.00091.651.25–2.170.0004
       Biologic treatmentNot applicable0.880.12–6.310.90041.870.60–5.850.2821
      Psoriasis with PsA3.101.905.06<0.00012.391.633.50<0.00012.281.673.11<0.0001
       Topical treatment2.631.37–5.07<0.00012.281.40–3.710.00092.401.65–3.51<0.0001
       Systemic nonbiologic treatment4.112.13–7.93<0.00012.791.61–4.820.00022.291.42–3.700.0007
       Biologic treatmentNot applicableNot applicableNot applicable
      Adjusted for age, sex, socioeconomic status, smoking, and alcohol abuse. Bold text indicates “all psoriasis patients” regardless of whether they receive topical, systemic nonbiologic, or biologic therapy.
      Abbreviations: CD, Crohn disease; CI, confidence interval; HR, hazard ratio.

       Ulcerative colitis

      During the study period, 504/870/1274 and 325/546/778 patients with psoriasis and general population referents, respectively, developed definite/probable/possible UC. The incidence of definite UC was 3.17 (95% CI = 2.90–3.46) among patients with psoriasis and 2.08 (95% CI = 1.87–2.32) in the general population. Comparable IRs were seen among patients receiving topical and systemic nonbiologic therapy, whereas lower IRs (although with wide and overlapping CIs) were seen for psoriasis treated with biologics (Table 2). The IRs in different age groups are presented in Supplementary Table S3 online. In adjusted models, there was a significantly increased risk of UC in patients with psoriasis (definite UC: aHR = 1.49, 95% CI = 1.30–1.71), although the risk of definite UC reached statistical significance only in patients without PsA (aHR = 1.50, 95% CI = 1.30–1.73) but not in patients with concurrent PsA (aHR = 1.29, 95% CI = 0.85–1.98, P = 0.2341) (Table 4). Among psoriasis patients with rheumatologist-verified PsA, the aHR of UC was 1.22 (95% CI = 0.80–1.87, P = 0.3589).
      Table 4HRs of the risk of ulcerative colitis in patients with psoriasis compared with the general population
      Definite UCProbable UCPossible UC
      Adjusted HR95% CIP-ValueAdjusted HR95% CIP-ValueAdjusted HR95% CIP-Value
      Any psoriasis1.491.301.71<0.00011.521.371.70<0.00011.561.431.71<0.0001
       Topical treatment1.491.29–1.72<0.00011.521.36–1.70<0.00011.551.42–1.70<0.0001
       Systemic nonbiologic treatment1.511.14–2.010.00411.541.24–1.92<0.00011.651.38–1.97<0.0001
       Biologic treatment1.230.39–3.860.71971.850.84–4.160.13561.130.47–2.740.7816
      Psoriasis without PsA1.501.301.73<0.00011.511.351.68<0.00011.531.391.67<0.0001
       Topical treatment1.491.29–1.72<0.00011.501.34–1.67<0.00011.521.39–1.67<0.0001
       Systemic nonbiologic treatment1.671.24–2.250.00071.581.25–2.000.00011.591.31–1.94<0.0001
       Biologic treatment1.230.31–4.970.76841.830.68–4.910.23071.360.51–3.650.5370
      Psoriasis with PsA1.290.851.980.23411.811.352.42<0.00012.211.772.77<0.0001
       Topical treatment1.580.97–2.590.06852.061.45–2.91<0.00012.421.85–3.18<0.0001
       Systemic nonbiologic treatment0.850.38–1.920.69621.390.83–2.330.21151.991.38–2.880.0003
       Biologic treatment1.290.18–9.300.80102.090.62–4.500.30080.770.11–5.520.7968
      Adjusted for age, sex, socioeconomic status, smoking, and alcohol abuse. Bold text indicates “all psoriasis patients” regardless of whether they receive topical, systemic nonbiologic, or biologic therapy.
      Abbreviations: CI, confidence interval; HR, hazard ratio; UC, ulcerative colitis.

       Distribution and characteristics

      Uses of different systemic nonbiologic and biologic therapies are presented in Supplementary Table S4 online. Among patients with definite IBD, the UC-to-CD ratio was 2.8 in the general population and 2.3 in patients with psoriasis (P = 0.105). The highest age-specific IR estimate (per 10,000 person-years) of CD was in women with psoriasis younger than 30 years (IR estimate = 4.28, 95% CI = 3.14–5.83), whereas the highest IR estimate of UC was seen in men with psoriasis aged 30–40 years (IR estimate = 5.13; 95% CI = 3.36–6.81) (Figure 2a and b). Surprisingly, mean time to diagnosis of CD, but not UC, was significantly longer among patients with psoriasis, compared with the general population, even among patients receiving only topical therapy (see Supplementary Table S5 online). However, for patients receiving systemic nonbiologic and especially biologic therapy, time to CD and UC diagnosis was significantly longer than the general population. Among patients with definite IBD, 66.6% of CD patients and 75.8% of UC patients had data specifying anatomical location, whereas the remaining patients were recorded as “unspecified” (International Classification of Diseases, 10th revision [ICD-10] codes K50.9 and K51.9, respectively). Although there were some numerical differences in anatomical involvement of CD or UC among patients with psoriasis and the general population, none of these differences were statistically significant (Table 5). Among patients developing definite CD, 9.8% (psoriasis) and 16.5% (general population) had a family history of either CD or UC (P = 0.127), whereas a positive family history was seen in 7.0% (psoriasis) and 8.2% (general population) of individuals who developed definite UC during the study, respectively (P = 0.612). Using patients without psoriasis as a reference, risk of CD, but not UC, was higher among patients with longer psoriasis duration (see Supplementary Table S6 online). Sensitivity analyses with additional adjustment for use of nonsteroidal anti-inflammatory drugs, systemic antibiotics, and oral contraceptives yielded similar findings compared with our primary analyses (see Supplementary Table S7 online). Furthermore, use of a different reference population where non-psoriasis individuals were required to have been seen in the Danish health care system within 30 days on the corresponding psoriasis patients index date did not significantly alter the findings of our primary analyses (see Supplementary Table S8 online).
      Figure thumbnail gr2
      Figure 2Age-specific incidence of Crohn disease and ulcerative colitis in men and women with psoriasis and in the general population. (a) Incidence of definite Crohn disease by sex and age in the general population and patients with psoriasis. (b) Incidence of definite ulcerative colitis by sex and age in the general population and patients with psoriasis. Significantly higher for women with psoriasis compared with women without psoriasis. ǂSignificantly higher for men with psoriasis compared with men without psoriasis. IR, incidence rate; y, year.
      Table 5Recorded disease manifestations of Crohn disease and ulcerative colitis among the general population and patients with psoriasis
      DiagnosisGeneral Population, %Psoriasis, %P-Value
      Crohn disease0.340
       Small intestine only36.142.8
       Large intestine only24.423.0
       Small and large intestines27.928.6
       Other areas only11.66.6
       Fistula12.118.20.131
      Ulcerative colitis
      1 Percentages do not add up to 100, because more locations may be reported in the same patient.
       Pancolitis60.267.40.066
       Proctitis34.327.80.085
       Proctosigmoiditis12.69.60.239
       Left-sided colitis7.59.60.351
       Left-sided proctocolitis2.81.60.395
       Other areas11.014.70.181
      1 Percentages do not add up to 100, because more locations may be reported in the same patient.

      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 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 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 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 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 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 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 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 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 (
      • Roberson E.D.
      • Bowcock A.M.
      Psoriasis genetics: breaking the barrier.
      ).
      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 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 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 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 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 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 (
      Correction.
      ;
      • 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 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 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 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 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 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 (
      • Gaist D.
      • Sorensen H.T.
      • Hallas J.
      The Danish prescription registries.
      ). Primary care services, including general practitioner and private clinics, are recorded in the Danish National Health Service Register (
      • 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 (

      Egeberg A, Thyssen JP, Wu JJ, Skov L. Risk of first-time and recurrent depression in patients with psoriasis—a population-based cohort study [e-pub ahead of print]. Br J Dermatol 2018b. https://doi.org/10.1111/bjd.17208.

      ). Information on tax-reported household income is recorded by Statistics Denmark (
      • Baadsgaard M.
      • Quitzau J.
      Danish registers on personal income and transfer payments.
      ), and information on age, sex, vital statistics, and migration status is available from the Civil Registration System (
      • 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 (

      Egeberg A, Thyssen JP, Wu JJ, Skov L. Risk of first-time and recurrent depression in patients with psoriasis—a population-based cohort study [e-pub ahead of print]. Br J Dermatol 2018b. https://doi.org/10.1111/bjd.17208.

      ). 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 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.

      Author Contributions

      AE had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: AE. Acquisition, analysis, and interpretation of data: all authors. Drafting of the manuscript: AE. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: AE. Obtained funding: none. Administrative, technical, or material support: AE. Study supervision: AE.

      Supplementary Material

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