BJD
British Journal of Dermatology
E P ID EMIOL O GY AN D HE AL TH S ER VI CE S R ESEA RCH
Risk of psoriasis in patients with childhood asthma: a Danish nationwide cohort study A. Egeberg,1 U. Khalid,1 G.H. Gislason,1 L. Mallbris,2 L. Skov3 and P.R. Hansen1 1 2
Department of Cardiology and 3Department of Dermato-allergology, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark Unit of Dermatology and Venereology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
Summary Correspondence Alexander Egeberg. E-mail: [email protected]
Accepted for publication 13 March 2015
Funding sources This work was supported by a grant from Pfizer. P.R.H. and U.K. are supported by a grant from the LEO Foundation. G.H.G. is supported by an unrestricted research scholarship from the Novo Nordisk Foundation. Pfizer, the Novo Nordisk Foundation and LEO Pharma had no influence on data collection, no access to the data, and no influence on the decision to submit.
Conflicts of interest A.E. and L.M. are currently employed by Pfizer. This research was made independently through the authors’ academic university affiliations. DOI 10.1111/bjd.13781
Background Psoriasis and asthma are disorders driven by inflammation. Psoriasis may carry an increased risk of asthma, but the reverse relationship has not been investigated. Objectives To investigate the risk of psoriasis in subjects with childhood asthma in a nationwide Danish cohort. Methods Data on all Danish individuals aged 6–14 years at study entry between 1 January 1997 and 31 December 2011 (n = 1 478 110) were linked at an individual level in nationwide registers. Incidence rates per 10 000 person-years were calculated, and incidence rate ratios (IRRs) adjusted for age, sex, concomitant medication and comorbidity were estimated by Poisson regression models. Results There were 21 725 cases of childhood asthma and 6586 incident cases of psoriasis. There were 5697 and 889 incident cases of mild and severe psoriasis, respectively. The incidence rates of overall, mild and severe psoriasis were 449, 388 and 061 for the reference population, and 595, 518 and 083 for subjects with childhood asthma, respectively. The IRRs for overall, mild and severe psoriasis were 394 [95% confidence interval (CI) 216–717], 503 (95% CI 248– 1021) and 227 (95% CI 061–842) for patients with childhood asthma. Conclusions Childhood asthma was associated with a significantly increased risk of psoriasis. Further studies are warranted to determine the clinical significance and effects of therapeutic interventions on this association.
What’s already known about this topic?
•
Psoriasis may be associated with increased risk of asthma, but the inverse relationship has not been investigated.
What does this study add?
•
Asthma in childhood is associated with a significantly increased risk of psoriasis.
Psoriasis is a chronic immunoinflammatory disease in which the inflammatory response is promoted by T helper (Th)1 and Th17 cells.1,2 Asthma results from chronic inflammation in the airways, and although it is believed to be driven primarily by Th2 cells, recent studies have demonstrated involvement of Th17 cells in asthma pathogenesis.3–5 While Th1- and Th2-driven diseases were previously thought to be inversely related, studies have shown increased risk of asthma in some Th1-driven diseases, for example rheumatoid arthritis and coeliac disease.6–8 However, only a few studies have examined the risk of asthma in patients with psoriasis, but the results are inconsistent and the risk of psoriasis in subjects with © 2015 British Association of Dermatologists
asthma has not been explored.9–11 The incidence and prevalence of asthma are highest during childhood, and environmental factors such as smoking are more likely to play a role in adult asthma pathogenesis.12 We therefore investigated the risk of psoriasis in subjects with childhood asthma in a nationwide cohort of the Danish population.
Materials and methods Conduct of this study was in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) recommendations.13 Study approval was obtained British Journal of Dermatology (2015) 173, pp159–164
159
160 Psoriasis in childhood asthmatics, A. Egeberg et al.
from the Danish Data Protection Agency (reference 2007-580015/internal reference GEH-2014-018/I-Suite 02736), and registry studies are exempted from review by an ethics committee in Denmark. Tax-supported health care and partial reimbursement of patient expenditures for a variety of prescribed drugs are provided to all residents in Denmark. Medication dispensed from pharmacies in Denmark is recorded in the Danish Registry of Medicinal Products Statistics, in which information on drugs – including drug class according to the international Anatomical Therapeutic Chemical (ATC) classification, date of dispensing, dosage, formulation and quantity – has been recorded with high accuracy since 1994.14 The Danish National Patient Register contains information on 994% of all hospital admissions, procedures and diagnoses since 1978.15 The register used the International Classification of Diseases 8th revision (ICD-8) until 1994, and the 10th revision (ICD-10) from 1994. Data from all of these registries can be linked on an individual level by use of the unique personal civil registration number ascribed to all Danes at birth. This nationwide cohort study included all Danish individuals aged 6–14 years at study entry from 1 January 1997 to either 31 December 2011 or occurrence of an end point, migration or death from any cause. Patients with ambiguous or missing information (e.g. missing date of birth) were excluded from the cohort, and patients with prevalent asthma or psoriasis were excluded in order to determine the temporal relationship between exposure and outcome. Childhood asthma was defined by the first diagnosis of asthma (ICD-10 code J45) that occurred at age 6–14 years. The diagnosis for this specific age group has been validated in the Danish National Patient Register, with a sensitivity of 90% and a specificity of 99%.16 We identified patients with mild psoriasis by their second dispensed prescription of topical vitamin D analogues (ATC code D05AX), which is the preferred first-line treatment for mild psoriasis in Denmark. Patients with severe psoriasis were classified by their third inpatient or outpatient hospital ICD-10 code for psoriasis (ICD-10 L40) or psoriatic arthritis (ICD-10 M070–M073). We have previously used and validated this method for psoriasis severity classification, where severe psoriasis represented a mean Psoriasis Area and Severity Index score of 10.17–19 Baseline treatment (up to 6 months prior to study inclusion) with the following drugs that have been linked to psoriasis (or conditions more frequently occurring in patients with asthma) was determined: antimalarial drugs (P01B), beta-blockers (C07), nonsteroidal anti-inflammatory drugs (NSAIDs) (M01AB) and statins (C10A).20 Comorbidities were described at study entry and up to 5 years previously based on ICD-10 codes. Statistical analysis SAS statistical software version 9.2 (SAS Institute Inc., Cary, NC, U.S.A.) and Stata software version 11.0 (StataCorp, College Station, TX, U.S.A.) were used to summarize incidence rates per 10 000 patient years, and to estimate incidence rate British Journal of Dermatology (2015) 173, pp159–164
ratios (IRRs) by Poisson regression. All statistical tests were conducted using a level of significance of 005, and results are reported with 95% confidence intervals (CIs) where applicable. To ensure accurate registration of time at risk, exposures to psoriasis and asthma were included as time-dependent variables, so the patients with asthma were considered to be at risk of psoriasis only from the time when they fulfilled the asthma diagnosis. We calculated IRRs as crude, age- and sexadjusted, and fully adjusted (in which age, sex, comorbidities and use of drugs associated with psoriasis were included).21 Sensitivity analyses were performed with a less conservative classification of patients with psoriasis, in which patients with mild psoriasis were classified at the time of their first prescription of topical vitamin D analogues, and patients with severe psoriasis were classified at the time of their first inpatient or outpatient hospitalization for psoriasis. This less conservative criterion for psoriasis diagnosis was chosen to assess the potential impact of high healthcare consumption inherent in the primary inclusion criteria. Childhood asthma could potentially have brought patients under closer medical scrutiny, which may have led to earlier ascertainment of psoriasis. To evaluate the effect of surveillance bias arising from being treated for childhood asthma, we undertook analyses (identical to our primary analyses) in which the exposure was a childhood diagnosis of epilepsy (ICD-10 codes G40–G41), as epilepsy has no apparent relationship with psoriasis.
Results The final cohort comprised 1 478 110 Danish citizens aged 6–14 years at study entry, including 21 725 patients with asthma (Table 1; Fig. 1). In total 6586 individuals developed psoriasis during followup, of whom 5697 and 889 had mild and severe psoriasis, respectively. Of these, 6499 instances of psoriasis occurred in the reference population and 87 occurred in individuals with childhood asthma. The mean time to diagnosis of psoriasis was 99 50 years for the reference population and 49 65 years for the asthma cohort. In the reference population and the asthma cohort the respective incidence rates per 10 000 person-years for overall psoriasis were 449 (95% CI 438–460) and 594 (95% CI 481–734), for mild psoriasis 388 (95% CI 378–399) and 518 (95% CI 413–649) and for severe psoriasis 061 (95% CI 057–065) and 083 (95% CI 047–146) (Table 2). In patients with asthma, the fully adjusted IRRs of overall, mild and severe psoriasis were 394 (95% CI 216–717), 503 (95% CI 248–1021) and 227 (95% CI 061–843), respectively (Table 3). In sensitivity analyses with altered criteria for classification of patients with mild and severe psoriasis, no significant changes in risk were observed compared with our primary analyses (data not shown). In the analyses that assessed the potential for surveillance bias, there was no significant increase in the risk of either overall, mild or severe psoriasis in subjects with childhood epilepsy (not shown). © 2015 British Association of Dermatologists
Psoriasis in childhood asthmatics, A. Egeberg et al. 161 Table 1 Baseline characteristics of the study population
Total number Age (years), mean SD Female Male Comorbidity Sleep apnoea Chronic sinusitis Chronic rhinitis GERD Medications Antimalarial drugs Beta-blockers Cholesterol-lowering drugs NSAIDs
Reference population
Asthma cohort
1 456 385 73 23 720 387 (495) 735 998 (505)
21 725 66 14 8503 (391) 13 222 (609)
1195 133 272 387
(008) (001) (002) (003)
770 (005) 275 (002) 17 (< 001) 556 (004)
28 4 18 20
(013) (002) (008) (009)
13 (006) 7 (003) 0 (0) 5 (002)
Values are n (%) unless stated otherwise. GERD, gastro-oesophageal reflux disease; NSAID, nonsteroidal anti-inflammatory drug.
Table 2 Incidence rates of psoriasis per 10 000 person-years in patients with childhood asthma compared with the reference population
Overall psoriasis Number of events Person-years Incidence rate 95% CI Mild psoriasis Number of events Person-years Incidence rate 95% CI Severe psoriasis Number of events Person-years Incidence rate 95% CI
Reference population
Asthma cohort
6499 14 471 693 449 438–460
87 144 816 594 481–734
5622 14 473 657 388 378–399
75 144 852 518 413–649
877 14 494 141 061 057–065
12 145 071 083 047–146
CI, confidence interval.
Fig 1. Study flowchart.
Discussion In this nationwide cohort study with a maximum follow-up of 15 years, we found an increased risk of incident psoriasis in patients with a childhood diagnosis of asthma. The increased risk remained consistent after adjustment for possible confounding factors and in sensitivity analyses. To the © 2015 British Association of Dermatologists
best of our knowledge, this is the first study to examine the risk of psoriasis in patients with childhood asthma. While psoriasis is generally thought to be promoted and maintained by Th1 cells, asthma is considered to be an atopic Th2-driven disorder. However, the traditional Th1/Th2 paradigm, which claims that diseases driven by Th1 and Th2 cells are inversely related due to immune cross-regulation, has been British Journal of Dermatology (2015) 173, pp159–164
162 Psoriasis in childhood asthmatics, A. Egeberg et al. Table 3 Incidence rate ratios (IRRs) of psoriasis in patients with childhood asthma IRR
95% CI
Crude estimates Risk of overall psoriasis 385 215–690 Risk of mild psoriasis 485 243–969 Risk of severe psoriasis 233 066–824 Adjusted for age and sex Risk of overall psoriasis 394 216–717 Risk of mild psoriasis 503 248–1021 Risk of severe psoriasis 227 061–842 Adjusted for age, sex, comorbidities and medication Risk of overall psoriasis 394 216–716 Risk of mild psoriasis 503 248–1020 Risk of severe psoriasis 227 061–843
P-value < 0001 < 0001 019 < 0001 < 0001 022 < 0001 < 0001 022
CI, confidence interval.
questioned in recent years. For example, animal models have demonstrated simultaneous expression of Th1 and Th2 cytokines within the same T cell.22 Moreover, studies have indicated that Th1- and Th2-driven diseases can coexist, and a parallel increase in the prevalence of asthma and certain Th1driven diseases (including psoriasis) has been observed.8,23–29 Along this line, a recent population-based cohort study reported that patients with rheumatoid arthritis (a Th1-driven disease) had a significantly increased risk of asthma compared with their healthy peers.6 Also, the contemporary view of the immune pathogenesis of psoriasis has shifted focus from Th1 to Th17 cells, potentially supporting the association with asthma, a heterogeneous disease with different phenotypes, in which an increase in Th17 cells is associated with more severe disease and less responsiveness to corticosteroids.2,30–33 Indeed, Th17-associated cytokines, such interleukin-17A and the interleukin-17 receptor A, are currently being investigated as therapeutic targets in both psoriasis and asthma.4,34 To our knowledge, only a few studies have examined the possible association of asthma and psoriasis (either cross-sectional investigations or studies analysing the risk of asthma in patients with psoriasis, not vice versa), and these have yielded inconsistent results. One Swedish study found an association between psoriasis and asthma in women but not in men.9 However, this study had a smaller sample size than our study, and was based exclusively on hospitalization rates. Very recently, two studies on the association between asthma and psoriasis have been published. A study from Taiwan examined the risk of asthma in a retrospective cohort of Asian patients with psoriasis.11 The study found a 38% increased risk of asthma compared with individuals without psoriasis. However, the study included only patients aged ≥ 20 years, and did not adjust for important confounding factors such as use of concomitant medication. Another Danish team studied the association between asthma and psoriasis in 34 781 Danish twins, aged 20–71 years, and also found a significantly increased risk of asthma in patients with psoriasis, after adjustment for age, sex, smoking, body British Journal of Dermatology (2015) 173, pp159–164
mass index and chronic obstructive pulmonary disease.10 Interestingly, in that study the increased risk was predominantly for nonatopic asthma, and was observed primarily for asthma with late onset (≥ 18 years). Therefore, the current sum of evidence suggests that the aetiologies of psoriasis and asthma may be more closely linked than previously believed, and the apparent bidirectionality of the risk between the two diseases supports the existence of shared underlying mechanisms, in which Th17 cells would appear likely to play a role.2,10,11,30–33 Interestingly, while the risks of overall and mild psoriasis were significantly increased in patients with childhood asthma, the risk of severe psoriasis in these patients was not significantly increased (P = 022). Whether this observation was due to the low number of events (n = 12) or whether, for example, the severity of psoriasis is affected by effective treatment of previous or concurrent asthma warrants further studies. It is recognized that patients with psoriasis have increased risk of cardiovascular disease including ischaemic stroke, and atherosclerosis is traditionally also perceived to be a Th1-driven disease.18,19,35 In this regard, and in potential accord with our present results, it is interesting to note that studies have suggested that patients with asthma may be at increased risk of coronary heart disease and stroke.36–39 Although the systemic inflammation associated with asthma and atherosclerosis has been among the suspected culprits underlying this association, research has also suggested that this risk may be mediated, in part, by cardiotoxic effects of b-2-agonists.40 Notwithstanding these considerations, our novel results suggest that patients with asthma may be at increased risk of psoriasis, and whether each of the two adds incrementally to cardiovascular risk in individuals with both of these diseases deserves further study. The administrative registers used in this study did not contain information on potentially important confounders, such as physical activity, body mass index and smoking status. Also, data on the socioeconomic status of the children, where low status has been linked to obesity and asthma, were not available to us.41,42 Obesity has been associated with increased risk of asthma and psoriasis, and weight loss has been shown to improve substantially the clinical status of patients with asthma.43,44 Also, smoking may be an independent risk factor for the development of psoriasis and asthma, but individuals in our cohort were included between the ages of 6 and 14 years, where the proportion of smokers is very low in Denmark.44,45 Although it is well established that asthma is more common in children, the prevalence of asthma varies greatly between different ethnic populations, and striking variations in the prevalence of asthma are observed across different income groups.12 Furthermore, regular use of certain drugs, for example NSAIDs, has been shown to increase the risk of asthma and psoriasis, which we attempted to adjust for in our study.46 In addition, the Danish population is predominantly of white descent, which may limit the extrapolation of the results to other ethnic groups. Important strengths of the study include the large sample size, long and complete fol© 2015 British Association of Dermatologists
Psoriasis in childhood asthmatics, A. Egeberg et al. 163
low-up, use of nationwide medical registries and the use of validated information on exposure and outcome measures, whereby bias related to sex, age and healthcare insurance are virtually eliminated. Finally, the baseline exclusion of subjects with prevalent psoriasis and asthma ensured accurate allocation of time at risk and evaluation of the temporal relationship between exposure and outcome. In conclusion, we found that childhood asthma was associated with a significantly increased risk of incident psoriasis. The clinical significance and effects of therapeutic interventions on this association warrant further studies.
References 1 Miossec P, Kolls JK. Targeting IL-17 and Th17 cells in chronic inflammation. Nat Rev Drug Discov 2012; 11:763–76. 2 Di Cesare A, Di Meglio P, Nestle FO. The IL-23/Th17 axis in the immunopathogenesis of psoriasis. J Invest Dermatol 2009; 129:1339–50. 3 Fanta CH. Asthma. N Engl J Med 2009; 360:1002–14. 4 Newcomb DC, Peebles RS Jr. Th17-mediated inflammation in asthma. Curr Opin Immunol 2013; 25:755–60. 5 Oboki K, Ohno T, Saito H, Nakae S. Th17 and allergy. Allergol Int 2008; 57:121–34. 6 Shen TC, Lin CL, Wei CC et al. The risk of asthma in rheumatoid arthritis: a population-based cohort study. QJM 2014; 107:435– 42. 7 Ludvigsson JF, Hemminki K, Wahlstr€ om J, Almqvist C. Celiac disease confers a 1.6-fold increased risk of asthma: a nationwide population-based cohort study. J Allergy Clin Immunol 2011; 127:1071–3. 8 Kero J, Gissler M, Hemminki E, Isolauri E. Could TH1 and TH2 diseases coexist? Evaluation of asthma incidence in children with coeliac disease, type 1 diabetes, or rheumatoid arthritis: a register study. J Allergy Clin Immunol 2001; 108:781–3. 9 Lindegard B. Diseases associated with psoriasis in a general population of 159,200 middle-aged, urban, native Swedes. Dermatologica 1986; 172:298–304. 10 Lonnberg AS, Skov L, Skytthe A et al. Asthma in patients with psoriasis. Br J Dermatol 2015; 172:1660–1661. 11 Fang HY, Liao WC, Lin CL et al. Association between psoriasis and asthma: a population-based retrospective cohort analysis. Br J Dermatol 2015; 171:1066–71. 12 Lai CK, Beasley R, Crane J et al. Global variation in the prevalence and severity of asthma symptoms: phase three of the International Study of Asthma and Allergies in Childhood (ISAAC). Thorax 2009; 64:476–83. 13 von Elm E, Altman DG, Egger M et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet 2007; 370:1453–7. 14 Gaist D, Sorensen HT, Hallas J. The Danish prescription registries. Dan Med Bull 1997; 44:445–8. 15 Andersen TF, Madsen M, Jørgensen J et al. The Danish National Hospital Register. A valuable source of data for modern health sciences. Dan Med Bull 1999; 46:263–8. 16 Moth G, Vedsted P, Schiotz PO. National registry diagnoses agree with medical records on hospitalized asthmatic children. Acta Paediatr 2007; 96:1470–3. 17 Ahlehoff O, Skov L, Gislason G et al. Cardiovascular outcomes and systemic anti-inflammatory drugs in patients with severe psoriasis:
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5-year follow-up of a Danish nationwide cohort. J Eur Acad Dermatol Venereol 2015; 29:1128–1134. Ahlehoff O, Gislason GH, Charlot M et al. Psoriasis is associated with clinically significant cardiovascular risk: a Danish nationwide cohort study. J Intern Med 2011; 270:147–57. Ahlehoff O, Gislason GH, Jørgensen CH et al. Psoriasis and risk of atrial fibrillation and ischaemic stroke: a Danish Nationwide Cohort Study. Eur Heart J 2012; 33:2054–64. Basavaraj KH, Ashok NM, Rashmi R, Praveen TK. The role of drugs in the induction and/or exacerbation of psoriasis. Int J Dermatol 2010; 49:1351–61. Nuttall M, van der Meulen J, Emberton M. Charlson scores based on ICD-10 administrative data were valid in assessing comorbidity in patients undergoing urological cancer surgery. J Clin Epidemiol 2006; 59:265–73. Assenmacher M, L€ ohning M, Scheffold A et al. Commitment of individual Th1-like lymphocytes to expression of IFN-c versus IL-4 and IL-10: selective induction of IL-10 by sequential stimulation of naive Th cells with IL-12 and IL-4. J Immunol 1998; 161:2825–32. Lindberg E, Lindquist B, Holmquist L, Hildebrand H. Inflammatory bowel disease in children and adolescents in Sweden, 1984– 1995. J Pediatr Gastroenterol Nutr 2000; 30:259–64. Phavichitr N, Cameron DJ, Catto-Smith AG. Increasing incidence of Crohn’s disease in Victorian children. J Gastroenterol Hepatol 2003; 18:329–32. Dahlquist G, Mustonen L. Analysis of 20 years of prospective registration of childhood onset diabetes time trends and birth cohort effects. Swedish Childhood Diabetes Study Group. Acta Paediatr 2000; 89:1231–7. Simpson CR, Anderson WJ, Helms PJ et al. Coincidence of immune-mediated diseases driven by Th1 and Th2 subsets suggests a common aetiology. A population-based study using computerized general practice data. Clin Exp Allergy 2002; 32:37–42. Sheikh A, Smeeth L, Hubbard R. There is no evidence of an inverse relationship between TH2-mediated atopy and TH1-mediated autoimmune disorders: lack of support for the hygiene hypothesis. J Allergy Clin Immunol 2003; 111:131–5. Icen M, Crowson CS, McEvoy MT et al. Trends in incidence of adult-onset psoriasis over three decades: a population-based study. J Am Acad Dermatol 2009; 60:394–401. Danielsen K, Olsen AO, Wilsgaard T, Furberg AS. Is the prevalence of psoriasis increasing? A 30-year follow-up of a population-based cohort. Br J Dermatol 2013; 168:1303–10. Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. Nature 2007; 445:866–73. Borish L, Culp JA. Asthma: a syndrome composed of heterogeneous diseases. Ann Allergy Asthma Immunol 2008; 101:1–8. Wenzel SE. Asthma: defining of the persistent adult phenotypes. Lancet 2006; 368:804–13. Hogan SP, Rosenberg HF, Moqbel R et al. Eosinophils: biological properties and role in health and disease. Clin Exp Allergy 2008; 38:709–50. Lonnberg AS, Zachariae C, Skov L. Targeting of interleukin-17 in the treatment of psoriasis. Clin Cosmet Investig Dermatol 2014; 7:251–9. Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol 2011; 12:204–12. Onufrak SJ, Abramson JL, Austin HD et al. Relation of adult-onset asthma to coronary heart disease and stroke. Am J Cardiol 2008; 101:1247–52. Onufrak S, Abramson J, Vaccarino V. Adult-onset asthma is associated with increased carotid atherosclerosis among women in the Atherosclerosis Risk in Communities (ARIC) study. Atherosclerosis 2007; 195:129–37.
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164 Psoriasis in childhood asthmatics, A. Egeberg et al. 38 Iribarren C, Tolstykh IV, Miller MK et al. Adult asthma and risk of coronary heart disease, cerebrovascular disease, and heart failure: a prospective study of 2 matched cohorts. Am J Epidemiol 2012; 176:1014–24. 39 Yun HD, Knoebel E, Fenta Y et al. Asthma and proinflammatory conditions: a population-based retrospective matched cohort study. Mayo Clin Proc 2012; 87:953–60. 40 Appleton SL, Ruffin RE, Wilson DH et al. Cardiovascular disease risk associated with asthma and respiratory morbidity might be mediated by short-acting b2-agonists. J Allergy Clin Immunol 2009; 123:124–30.e1. 41 Shrewsbury V, Wardle J. Socioeconomic status and adiposity in childhood: a systematic review of cross-sectional studies 1990– 2005. Obesity (Silver Spring) 2008; 16:275–84.
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42 Burr ML, Verrall C, Kaur B. Social deprivation and asthma. Respir Med 1997; 91:603–8. 43 Ford ES. The epidemiology of obesity and asthma. J Allergy Clin Immunol 2005; 115:897–909. 44 Duarte GV, Oliveira Mde F, Cardoso TM et al. Association between obesity measured by different parameters and severity of psoriasis. Int J Dermatol 2013; 52:177–81. 45 Rasmussen M, Due P, Andersen A et al. [Smoking trends in 11–15year-olds from 1988 to 2006]. Ugeskr Laeger 2008; 170:736–9 (in Danish). 46 Thomsen SF, Kyvik KO, Skadhauge LR et al. Regular use of nonsteroidal anti-inflammatory drugs increases the risk of adult-onset asthma: a population-based follow-up study. Clin Respir J 2009; 3:82–4.
© 2015 British Association of Dermatologists
British Journal of Dermatology
E P ID EMIOL O GY AN D HE AL TH S ER VI CE S R ESEA RCH
Risk of psoriasis in patients with childhood asthma: a Danish nationwide cohort study A. Egeberg,1 U. Khalid,1 G.H. Gislason,1 L. Mallbris,2 L. Skov3 and P.R. Hansen1 1 2
Department of Cardiology and 3Department of Dermato-allergology, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark Unit of Dermatology and Venereology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
Summary Correspondence Alexander Egeberg. E-mail: [email protected]
Accepted for publication 13 March 2015
Funding sources This work was supported by a grant from Pfizer. P.R.H. and U.K. are supported by a grant from the LEO Foundation. G.H.G. is supported by an unrestricted research scholarship from the Novo Nordisk Foundation. Pfizer, the Novo Nordisk Foundation and LEO Pharma had no influence on data collection, no access to the data, and no influence on the decision to submit.
Conflicts of interest A.E. and L.M. are currently employed by Pfizer. This research was made independently through the authors’ academic university affiliations. DOI 10.1111/bjd.13781
Background Psoriasis and asthma are disorders driven by inflammation. Psoriasis may carry an increased risk of asthma, but the reverse relationship has not been investigated. Objectives To investigate the risk of psoriasis in subjects with childhood asthma in a nationwide Danish cohort. Methods Data on all Danish individuals aged 6–14 years at study entry between 1 January 1997 and 31 December 2011 (n = 1 478 110) were linked at an individual level in nationwide registers. Incidence rates per 10 000 person-years were calculated, and incidence rate ratios (IRRs) adjusted for age, sex, concomitant medication and comorbidity were estimated by Poisson regression models. Results There were 21 725 cases of childhood asthma and 6586 incident cases of psoriasis. There were 5697 and 889 incident cases of mild and severe psoriasis, respectively. The incidence rates of overall, mild and severe psoriasis were 449, 388 and 061 for the reference population, and 595, 518 and 083 for subjects with childhood asthma, respectively. The IRRs for overall, mild and severe psoriasis were 394 [95% confidence interval (CI) 216–717], 503 (95% CI 248– 1021) and 227 (95% CI 061–842) for patients with childhood asthma. Conclusions Childhood asthma was associated with a significantly increased risk of psoriasis. Further studies are warranted to determine the clinical significance and effects of therapeutic interventions on this association.
What’s already known about this topic?
•
Psoriasis may be associated with increased risk of asthma, but the inverse relationship has not been investigated.
What does this study add?
•
Asthma in childhood is associated with a significantly increased risk of psoriasis.
Psoriasis is a chronic immunoinflammatory disease in which the inflammatory response is promoted by T helper (Th)1 and Th17 cells.1,2 Asthma results from chronic inflammation in the airways, and although it is believed to be driven primarily by Th2 cells, recent studies have demonstrated involvement of Th17 cells in asthma pathogenesis.3–5 While Th1- and Th2-driven diseases were previously thought to be inversely related, studies have shown increased risk of asthma in some Th1-driven diseases, for example rheumatoid arthritis and coeliac disease.6–8 However, only a few studies have examined the risk of asthma in patients with psoriasis, but the results are inconsistent and the risk of psoriasis in subjects with © 2015 British Association of Dermatologists
asthma has not been explored.9–11 The incidence and prevalence of asthma are highest during childhood, and environmental factors such as smoking are more likely to play a role in adult asthma pathogenesis.12 We therefore investigated the risk of psoriasis in subjects with childhood asthma in a nationwide cohort of the Danish population.
Materials and methods Conduct of this study was in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) recommendations.13 Study approval was obtained British Journal of Dermatology (2015) 173, pp159–164
159
160 Psoriasis in childhood asthmatics, A. Egeberg et al.
from the Danish Data Protection Agency (reference 2007-580015/internal reference GEH-2014-018/I-Suite 02736), and registry studies are exempted from review by an ethics committee in Denmark. Tax-supported health care and partial reimbursement of patient expenditures for a variety of prescribed drugs are provided to all residents in Denmark. Medication dispensed from pharmacies in Denmark is recorded in the Danish Registry of Medicinal Products Statistics, in which information on drugs – including drug class according to the international Anatomical Therapeutic Chemical (ATC) classification, date of dispensing, dosage, formulation and quantity – has been recorded with high accuracy since 1994.14 The Danish National Patient Register contains information on 994% of all hospital admissions, procedures and diagnoses since 1978.15 The register used the International Classification of Diseases 8th revision (ICD-8) until 1994, and the 10th revision (ICD-10) from 1994. Data from all of these registries can be linked on an individual level by use of the unique personal civil registration number ascribed to all Danes at birth. This nationwide cohort study included all Danish individuals aged 6–14 years at study entry from 1 January 1997 to either 31 December 2011 or occurrence of an end point, migration or death from any cause. Patients with ambiguous or missing information (e.g. missing date of birth) were excluded from the cohort, and patients with prevalent asthma or psoriasis were excluded in order to determine the temporal relationship between exposure and outcome. Childhood asthma was defined by the first diagnosis of asthma (ICD-10 code J45) that occurred at age 6–14 years. The diagnosis for this specific age group has been validated in the Danish National Patient Register, with a sensitivity of 90% and a specificity of 99%.16 We identified patients with mild psoriasis by their second dispensed prescription of topical vitamin D analogues (ATC code D05AX), which is the preferred first-line treatment for mild psoriasis in Denmark. Patients with severe psoriasis were classified by their third inpatient or outpatient hospital ICD-10 code for psoriasis (ICD-10 L40) or psoriatic arthritis (ICD-10 M070–M073). We have previously used and validated this method for psoriasis severity classification, where severe psoriasis represented a mean Psoriasis Area and Severity Index score of 10.17–19 Baseline treatment (up to 6 months prior to study inclusion) with the following drugs that have been linked to psoriasis (or conditions more frequently occurring in patients with asthma) was determined: antimalarial drugs (P01B), beta-blockers (C07), nonsteroidal anti-inflammatory drugs (NSAIDs) (M01AB) and statins (C10A).20 Comorbidities were described at study entry and up to 5 years previously based on ICD-10 codes. Statistical analysis SAS statistical software version 9.2 (SAS Institute Inc., Cary, NC, U.S.A.) and Stata software version 11.0 (StataCorp, College Station, TX, U.S.A.) were used to summarize incidence rates per 10 000 patient years, and to estimate incidence rate British Journal of Dermatology (2015) 173, pp159–164
ratios (IRRs) by Poisson regression. All statistical tests were conducted using a level of significance of 005, and results are reported with 95% confidence intervals (CIs) where applicable. To ensure accurate registration of time at risk, exposures to psoriasis and asthma were included as time-dependent variables, so the patients with asthma were considered to be at risk of psoriasis only from the time when they fulfilled the asthma diagnosis. We calculated IRRs as crude, age- and sexadjusted, and fully adjusted (in which age, sex, comorbidities and use of drugs associated with psoriasis were included).21 Sensitivity analyses were performed with a less conservative classification of patients with psoriasis, in which patients with mild psoriasis were classified at the time of their first prescription of topical vitamin D analogues, and patients with severe psoriasis were classified at the time of their first inpatient or outpatient hospitalization for psoriasis. This less conservative criterion for psoriasis diagnosis was chosen to assess the potential impact of high healthcare consumption inherent in the primary inclusion criteria. Childhood asthma could potentially have brought patients under closer medical scrutiny, which may have led to earlier ascertainment of psoriasis. To evaluate the effect of surveillance bias arising from being treated for childhood asthma, we undertook analyses (identical to our primary analyses) in which the exposure was a childhood diagnosis of epilepsy (ICD-10 codes G40–G41), as epilepsy has no apparent relationship with psoriasis.
Results The final cohort comprised 1 478 110 Danish citizens aged 6–14 years at study entry, including 21 725 patients with asthma (Table 1; Fig. 1). In total 6586 individuals developed psoriasis during followup, of whom 5697 and 889 had mild and severe psoriasis, respectively. Of these, 6499 instances of psoriasis occurred in the reference population and 87 occurred in individuals with childhood asthma. The mean time to diagnosis of psoriasis was 99 50 years for the reference population and 49 65 years for the asthma cohort. In the reference population and the asthma cohort the respective incidence rates per 10 000 person-years for overall psoriasis were 449 (95% CI 438–460) and 594 (95% CI 481–734), for mild psoriasis 388 (95% CI 378–399) and 518 (95% CI 413–649) and for severe psoriasis 061 (95% CI 057–065) and 083 (95% CI 047–146) (Table 2). In patients with asthma, the fully adjusted IRRs of overall, mild and severe psoriasis were 394 (95% CI 216–717), 503 (95% CI 248–1021) and 227 (95% CI 061–843), respectively (Table 3). In sensitivity analyses with altered criteria for classification of patients with mild and severe psoriasis, no significant changes in risk were observed compared with our primary analyses (data not shown). In the analyses that assessed the potential for surveillance bias, there was no significant increase in the risk of either overall, mild or severe psoriasis in subjects with childhood epilepsy (not shown). © 2015 British Association of Dermatologists
Psoriasis in childhood asthmatics, A. Egeberg et al. 161 Table 1 Baseline characteristics of the study population
Total number Age (years), mean SD Female Male Comorbidity Sleep apnoea Chronic sinusitis Chronic rhinitis GERD Medications Antimalarial drugs Beta-blockers Cholesterol-lowering drugs NSAIDs
Reference population
Asthma cohort
1 456 385 73 23 720 387 (495) 735 998 (505)
21 725 66 14 8503 (391) 13 222 (609)
1195 133 272 387
(008) (001) (002) (003)
770 (005) 275 (002) 17 (< 001) 556 (004)
28 4 18 20
(013) (002) (008) (009)
13 (006) 7 (003) 0 (0) 5 (002)
Values are n (%) unless stated otherwise. GERD, gastro-oesophageal reflux disease; NSAID, nonsteroidal anti-inflammatory drug.
Table 2 Incidence rates of psoriasis per 10 000 person-years in patients with childhood asthma compared with the reference population
Overall psoriasis Number of events Person-years Incidence rate 95% CI Mild psoriasis Number of events Person-years Incidence rate 95% CI Severe psoriasis Number of events Person-years Incidence rate 95% CI
Reference population
Asthma cohort
6499 14 471 693 449 438–460
87 144 816 594 481–734
5622 14 473 657 388 378–399
75 144 852 518 413–649
877 14 494 141 061 057–065
12 145 071 083 047–146
CI, confidence interval.
Fig 1. Study flowchart.
Discussion In this nationwide cohort study with a maximum follow-up of 15 years, we found an increased risk of incident psoriasis in patients with a childhood diagnosis of asthma. The increased risk remained consistent after adjustment for possible confounding factors and in sensitivity analyses. To the © 2015 British Association of Dermatologists
best of our knowledge, this is the first study to examine the risk of psoriasis in patients with childhood asthma. While psoriasis is generally thought to be promoted and maintained by Th1 cells, asthma is considered to be an atopic Th2-driven disorder. However, the traditional Th1/Th2 paradigm, which claims that diseases driven by Th1 and Th2 cells are inversely related due to immune cross-regulation, has been British Journal of Dermatology (2015) 173, pp159–164
162 Psoriasis in childhood asthmatics, A. Egeberg et al. Table 3 Incidence rate ratios (IRRs) of psoriasis in patients with childhood asthma IRR
95% CI
Crude estimates Risk of overall psoriasis 385 215–690 Risk of mild psoriasis 485 243–969 Risk of severe psoriasis 233 066–824 Adjusted for age and sex Risk of overall psoriasis 394 216–717 Risk of mild psoriasis 503 248–1021 Risk of severe psoriasis 227 061–842 Adjusted for age, sex, comorbidities and medication Risk of overall psoriasis 394 216–716 Risk of mild psoriasis 503 248–1020 Risk of severe psoriasis 227 061–843
P-value < 0001 < 0001 019 < 0001 < 0001 022 < 0001 < 0001 022
CI, confidence interval.
questioned in recent years. For example, animal models have demonstrated simultaneous expression of Th1 and Th2 cytokines within the same T cell.22 Moreover, studies have indicated that Th1- and Th2-driven diseases can coexist, and a parallel increase in the prevalence of asthma and certain Th1driven diseases (including psoriasis) has been observed.8,23–29 Along this line, a recent population-based cohort study reported that patients with rheumatoid arthritis (a Th1-driven disease) had a significantly increased risk of asthma compared with their healthy peers.6 Also, the contemporary view of the immune pathogenesis of psoriasis has shifted focus from Th1 to Th17 cells, potentially supporting the association with asthma, a heterogeneous disease with different phenotypes, in which an increase in Th17 cells is associated with more severe disease and less responsiveness to corticosteroids.2,30–33 Indeed, Th17-associated cytokines, such interleukin-17A and the interleukin-17 receptor A, are currently being investigated as therapeutic targets in both psoriasis and asthma.4,34 To our knowledge, only a few studies have examined the possible association of asthma and psoriasis (either cross-sectional investigations or studies analysing the risk of asthma in patients with psoriasis, not vice versa), and these have yielded inconsistent results. One Swedish study found an association between psoriasis and asthma in women but not in men.9 However, this study had a smaller sample size than our study, and was based exclusively on hospitalization rates. Very recently, two studies on the association between asthma and psoriasis have been published. A study from Taiwan examined the risk of asthma in a retrospective cohort of Asian patients with psoriasis.11 The study found a 38% increased risk of asthma compared with individuals without psoriasis. However, the study included only patients aged ≥ 20 years, and did not adjust for important confounding factors such as use of concomitant medication. Another Danish team studied the association between asthma and psoriasis in 34 781 Danish twins, aged 20–71 years, and also found a significantly increased risk of asthma in patients with psoriasis, after adjustment for age, sex, smoking, body British Journal of Dermatology (2015) 173, pp159–164
mass index and chronic obstructive pulmonary disease.10 Interestingly, in that study the increased risk was predominantly for nonatopic asthma, and was observed primarily for asthma with late onset (≥ 18 years). Therefore, the current sum of evidence suggests that the aetiologies of psoriasis and asthma may be more closely linked than previously believed, and the apparent bidirectionality of the risk between the two diseases supports the existence of shared underlying mechanisms, in which Th17 cells would appear likely to play a role.2,10,11,30–33 Interestingly, while the risks of overall and mild psoriasis were significantly increased in patients with childhood asthma, the risk of severe psoriasis in these patients was not significantly increased (P = 022). Whether this observation was due to the low number of events (n = 12) or whether, for example, the severity of psoriasis is affected by effective treatment of previous or concurrent asthma warrants further studies. It is recognized that patients with psoriasis have increased risk of cardiovascular disease including ischaemic stroke, and atherosclerosis is traditionally also perceived to be a Th1-driven disease.18,19,35 In this regard, and in potential accord with our present results, it is interesting to note that studies have suggested that patients with asthma may be at increased risk of coronary heart disease and stroke.36–39 Although the systemic inflammation associated with asthma and atherosclerosis has been among the suspected culprits underlying this association, research has also suggested that this risk may be mediated, in part, by cardiotoxic effects of b-2-agonists.40 Notwithstanding these considerations, our novel results suggest that patients with asthma may be at increased risk of psoriasis, and whether each of the two adds incrementally to cardiovascular risk in individuals with both of these diseases deserves further study. The administrative registers used in this study did not contain information on potentially important confounders, such as physical activity, body mass index and smoking status. Also, data on the socioeconomic status of the children, where low status has been linked to obesity and asthma, were not available to us.41,42 Obesity has been associated with increased risk of asthma and psoriasis, and weight loss has been shown to improve substantially the clinical status of patients with asthma.43,44 Also, smoking may be an independent risk factor for the development of psoriasis and asthma, but individuals in our cohort were included between the ages of 6 and 14 years, where the proportion of smokers is very low in Denmark.44,45 Although it is well established that asthma is more common in children, the prevalence of asthma varies greatly between different ethnic populations, and striking variations in the prevalence of asthma are observed across different income groups.12 Furthermore, regular use of certain drugs, for example NSAIDs, has been shown to increase the risk of asthma and psoriasis, which we attempted to adjust for in our study.46 In addition, the Danish population is predominantly of white descent, which may limit the extrapolation of the results to other ethnic groups. Important strengths of the study include the large sample size, long and complete fol© 2015 British Association of Dermatologists
Psoriasis in childhood asthmatics, A. Egeberg et al. 163
low-up, use of nationwide medical registries and the use of validated information on exposure and outcome measures, whereby bias related to sex, age and healthcare insurance are virtually eliminated. Finally, the baseline exclusion of subjects with prevalent psoriasis and asthma ensured accurate allocation of time at risk and evaluation of the temporal relationship between exposure and outcome. In conclusion, we found that childhood asthma was associated with a significantly increased risk of incident psoriasis. The clinical significance and effects of therapeutic interventions on this association warrant further studies.
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