BJD

British Journal of Dermatology

E P ID EMIOL O GY AN D HE AL TH S ER VI CE S R ESEA RCH

Association between depression and risk of atrial fibrillation and stroke in patients with psoriasis: 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 9 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, Novo Nordisk 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 performed independently through the authors’ academic university affiliations. *Plain language summary available online. DOI 10.1111/bjd.13778

Background Psoriasis and depression are associated with atrial fibrillation (AF) and stroke, but the influence of depression on the risk of stroke and AF in patients with psoriasis has not been examined. Objectives We investigated the impact of depression on the risk of stroke and AF in patients with psoriasis in a nationwide cohort. Methods Data on all Danish citizens aged ≥ 18 years between 1 January 1997 and 31 December 2011 (n = 5 251 888) were linked at the individual level in nationwide registers. Incidence rates (IRs) per 1000 person-years were calculated, and hazard ratios (HRs) adjusted for age, sex, concomitant medication and comorbidity were estimated by multivariate Cox regression models. Results There were 56 496 and 11 357 incident cases of mild and severe psoriasis, respectively. Incident depression occurred among 12 788 cases with mild and 3261 cases with severe psoriasis. IRs per 1000 patient-years of AF were 3
21, 5
02, 8
41, 5
39 and 7
41; and IRs of stroke were 2
62, 3
09, 6
71, 3
62 and 9
03 for the reference population, mild psoriasis without depression, mild psoriasis with depression, severe psoriasis without depression and severe psoriasis with depression, respectively. The respective HRs for new-onset AF were 1
14 [95% confidence interval (CI) 1
08–1
33], 1
19 (95% CI 1
06–1
33), 1
32 (95% CI 1
15–1
53) and 1
74 (95% CI 1.43–2
11), respectively. For stroke the HRs were 1
63 (95% CI 1
43–1
85) in patients with mild psoriasis and depression and 2
47 (95% CI 2
07–2
95) in patients with severe psoriasis and depression. Conclusions In patients with psoriasis, depression is associated with an increased risk of incident AF and stroke.

What’s already known about this topic?

•

Patients with psoriasis have increased risk of atrial fibrillation and stroke.

What does this study add?

• •

Depression was associated with increased risk of stroke, and an incremental increase in risk of atrial fibrillation in patients with psoriasis. No increased risk of stroke was observed in patients with psoriasis without depression.

Psoriasis is one of the most common immune-mediated inflammatory diseases, with a prevalence of 2–3% in Europeans.1 Psoriasis is driven mainly by T helper (Th)1 and Th17 © 2015 British Association of Dermatologists

lymphocytes, which contribute to a chronic systemic inflammatory state that is associated with increased risk of cardiovascular disease.2–5 In recent years, depression has been shown British Journal of Dermatology (2015) 173, pp471–479

471

472 Psoriasis, depression and risk of atrial fibrillation and stroke, A. Egeberg et al.

to include an inflammatory component that may share some of the same mediators seen in psoriasis, such as interleukin (IL)-2, IL-6, IL-12 and tumour necrosis factor (TNF)-a.6–8 Systemic inflammation is also a risk factor for both new-onset and recurrent atrial fibrillation (AF), and atrial infiltration of inflammatory cells has been observed in patients with AF.9–11 Moreover, in patients with persistent AF, depressive symptoms may predict recurrence of AF following cardioversion.12 Not only do patients with psoriasis have a significantly increased risk of depression, but depression is also suspected to be an independent risk factor for the development of psoriasis, arguing for a bidirectional relationship between the two diseases.13,14 However, while psoriasis has been associated with an increased risk of AF and ischaemic stroke,3 it is unclear whether the presence of depression increases the risk of AF and stroke in patients with psoriasis. Using a nationwide cohort of the Danish population, we therefore investigated the risk of AF and stroke in patients with psoriasis with or without depression.

Materials and methods Data sources and study population All Danish citizens have access to healthcare services free of charge, and it is possible to link data between Danish registries by using the unique personal identification number, which all citizens in Denmark are given at immigration or birth. The Danish National Patient Register contains information on hospital admissions, procedures and diagnosis since 1978, which provides researchers with detailed information on morbidity in patients.15 The registry used the International Classification of Diseases 8th revision (ICD-8) codes until 1994, when it switched to the current ICD-10 classification. For information on medication we used the Danish Registry of Medicinal Products Statistics, in which drugs are recorded according to the international Anatomical Therapeutic Chemical (ATC) classification.16 This registry governs partial reimbursement of drug expenses to pharmacies and patients, and contains complete and accurate data – for example date of dispensing, drug dosage, formulation and quantity – for all medications dispensed from Danish pharmacies since 1994. We included all Danish citizens aged ≥ 18 years in the study cohort, starting from 1 January 1997 until either 31 December 2011 or a primary end point (AF or stroke), migration or death from any cause (Fig. 1). We excluded patients with a history of psoriasis, AF, stroke, depression or use of antidepressants (ATC code N06A) prior to study inclusion, in order to determine better the relationship between onset of psoriasis and depression, and the time during which patients were at risk for AF or stroke. Patients with ambiguous or missing information (e.g. missing date of birth) were also excluded. Patients were classified as having mild psoriasis when they claimed their second prescription of a topical vitamin D derivate (ATC D05AX), and were classified with severe psoriasis at the time of the third inpatient or outpatient hospiBritish Journal of Dermatology (2015) 173, pp471–479

tal contact for psoriasis (ICD-10 code L40) or psoriatic arthritis (codes M070–M073). This method for psoriasis severity classification has previously been validated in 50 consecutive patients classified with severe psoriasis, where the mean Psoriasis Area and Severity Index score was 10.2 We classified patients as having depression when their second prescription of antidepressant medication (ATC N06A) was dispensed from a pharmacy. A recent study of more than 14 000 Danish citizens used the five-item World Health Organization Well-Being Index and the ICD-10 criteria to assess depression. The study found that of individuals who did not currently fit the criteria for clinical depression, only 4
7% received antidepressants.17 Based on ICD-10 codes, comorbidities were described by use of the Charlson Comorbidity Index at study inclusion and up to 5 years prior to study entry.18 As depression was classified exclusively as incident depression during follow-up, the rate of depression is not comparable with the occurrence of the baseline comorbidity described (Table 1). With information on the average gross annual income available from Statistics Denmark, we calculated an index from 0 to 4 of age-standardized socioeconomic status in the 5-year period prior to study inclusion. This study was approved by the Danish Data Protection Agency (reference 2007-58-0015). Approval from an ethics committee is not required for register studies in Denmark. Conduct of the study was in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) recommendations.19 Medical treatment From the Registry of Medicinal Products Statistics, we defined baseline treatment with the following drugs, by prescriptions dispensed in the last 6 months prior to study inclusion: angiotensin-converting enzyme inhibitors/angiotensin-2 receptor blockers (C09), antidiabetic drugs (A10), antithyroid medication (H03B), beta-blockers (C07), calcium channel blockers (C08), digoxin (C01AA05), methotrexate (L01BA01), platelet inhibitors (B01AC), spironolactone (C03D), statins (C10A), systemic glucocorticoids (H02AB), thiazides (C03A) and vitamin K antagonists (B01AA). Study end points The coprimary end points were the first diagnosis of AF (ICD8 codes 427.94 and 427.95, and ICD-10 code I48) and stroke (ICD-8 codes 432–436, and ICD-10 codes I63–64). These diagnoses were previously validated in the Danish National Patient Register.20,21 The risk of AF or stroke was investigated in separate analyses, and occurrence of AF in one analysis did not result in censoring of stroke in the other, and vice versa. Statistical analysis Baseline characteristics are presented as means with SDs and frequencies with percentages for categorical and continuous © 2015 British Association of Dermatologists

Psoriasis, depression and risk of atrial fibrillation and stroke, A. Egeberg et al. 473

Fig 1. Study flowchart. AF, atrial fibrillation.

variables, respectively. Incidence rates were summarized per 1000 patient-years at risk. To ensure accurate registration of time at risk, exposure to psoriasis was included as a timedependent variable, so the patients were considered to be at risk only from the time when they fulfilled the psoriasis diagnosis. Crude, age- and sex-adjusted, and fully adjusted (in which age, sex, socioeconomic status, comorbidities and use of concomitant medication were considered) hazard ratios (HRs) were estimated by use of Cox proportional-hazards models. To support our findings, we performed a range of sensitivity analyses as follows. Analysis A: we included admissions for only AF and stroke as primary diagnoses; analysis B: we excluded patients who used vitamin K antagonists at baseline and during follow-up, in an attempt to exclude unreported cases of prevalent AF; analysis C: we used a less conservative classification of patients with psoriasis where patients with mild psoriasis were classified at the time of their first prescription of vitamin D derivatives, and patients with severe psoriasis were classified at the time of their first inpatient or outpatient hospitalization for psoriasis (i.e. a design associated with fewer healthcare contacts and consequent reduction of surveillance bias for the patients); and analysis D: we used the latter design and also narrowed our definition of depression to © 2015 British Association of Dermatologists

include only patients with a hospital diagnosis of depression (ICD-10 F33–34), in order to diminish the contribution of patients treated with antidepressants for conditions other than depression. Two-tailed P-values < 0
05 were considered statistically significant. The results are reported with 95% confidence intervals (CIs), where applicable. Analyses were performed using the 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.).

Results Our cohort comprised a total of 5 251 888 Danish citizens aged ≥ 18 years, including 67 853 patients with psoriasis. Stratified by disease severity, the group of patients with mild psoriasis (n = 56 496) included 12 788 cases of depression, whereas the group with severe psoriasis (n = 11 357) had 3261 cases of depression. There was a comparable sex distribution in both the reference and psoriasis groups, but a slightly higher percentage of women among patients with psoriasis and concurrent depression (59
0% of patients with mild psoriasis with depression and 61
1% of patients with severe psoriasis and depression). In total 197 960 individuals British Journal of Dermatology (2015) 173, pp471–479

2 589 868 (50
0) 2
0  1
4

0
07  0
4

Men Socioeconomic

status, mean  SD Charlson

British Journal of Dermatology (2015) 173, pp471–479

13 618 (0
3)

45 497 (0
9)

10 857 (0
2)

dysrhythmias Congestive heart

failure Ischaemic heart

disease Peripheral vascular

39 912 (0
8) 96 698 (1
9)

3578 (0
1)

Digoxin Loop diuretics

Methotrexate

120 332 (2
3)

Calcium channel blockers

24 398 (0
5)

11 545 (0
2) 116 039 (2
2)

Antithyroid drugs Beta-blockers

Cholesterol-lowering drugs

112 153 (2
2) 63 705 (1
2)

100 081 (1
9)

22 189 (0
4)

Acetylsalicylic acid Antidiabetic drugs

Medications ACEI/ARB

Rheumatological disease

4151 (0
1)

15 545 (0
3)

Cardiac

disease Renal disease

28 659 (0
6) 59 559 (1
2)

Diabetes mellitus Cancer

Comorbidity COPD

20 924 (0
4)

2 594 167 (50
0)

mean  SD Women

Comorbidity Index, mean  SD

5 184 035 39
7  19
2

Total number Age (years),

Reference population

424 (0
6)

302 (0
5) 1041 (1
5)

520 (0
8)

1960 (2
9)

156 (0
2) 2068 (3
1)

1416 (2
1) 982 (1
5)

1768 (2
6)

450 (0
7)

44 (0
1)

127 (0
2)

701 (1
0)

107 (0
2)

211 (0
3)

440 (0
7) 747 (1
1)

209 (0
3)

0
07  0
4

33 470 (49
3) 2
5  1
3

34 383 (50
7)

67 853 42
9  16
2

305 (0
6)

199 (0
4) 662 (1
3)

362 (0
7)

1279 (2
5)

111 (0
2) 1371 (2
7)

943 (1
8) 638 (1
2)

1213 (2
3)

279 (0
5)

32 (0
1)

82 (0
2)

454 (0
9)

79 (0
2)

148 (0
3)

274 (0
5) 517 (1
0)

126 (0
2)

0
06  0
4

26 965 (52
0) 2
5  1
4

24 839 (48
0)

51 804 42
2  16
0

119 (0
7)

103 (0
6) 379 (2
4)

158 (1
0)

681 (4
2)

45 (0
3) 697 (4
3)

473 (3
0) 344 (2
1)

555 (3
5)

171 (1
1)

12 (0
1)

45 (0
3)

247 (1
5)

28 (0
2)

63 (0
4)

166 (1
0) 230 (1
4)

83 (0
5)

0
1  0
5

6505 (40
5) 2
4  1
3

9544 (59
5)

16 049 45
4  16
6

121 (0
2)

264 (0
5) 829 (1
5)

437 (0
8)

1660 (2
9)

126 (0
2) 1769 (3
1)

1218 (2
2) 791 (1
4)

1505 (2
7)

331 (0
6)

31 (0
1)

107 (0
2)

566 (1
0)

89 (0
2)

177 (0
3)

349 (0
6) 600 (1
1)

157 (0
3)

0
06  0
4

27 989 (49
5) 2
5  1
4

28 507 (50
5)

56 496 43
2  164

Total

Depression

Total

No depression

Mild psoriasis

Overall psoriasis

Table 1 Baseline characteristics of the study population

86 (0
2)

173 (0
4) 538 (1
2)

305 (0
7)

1104 (2
5)

84 (0
2) 1177 (2
7)

821 (1
9) 513 (1
2)

1045 (2
4)

206 (0
5)

23 (0
1)

68 (0
2)

370 (0
9)

65 (0
2)

124 (0
3)

215 (0
5) 423 (1
0)

92 (0
2)

0
05  0
3

22 751 (52
0) 2
5  1
4

20 957 (48
0)

43 708 42
3  16
2

No depression

35 (0
3)

91 (0
7) 291 (2
3)

132 (1
0)

556 (4
4)

42 (0
3) 592 (4
6)

398 (3
1) 278 (2
2)

460 (3
6)

125 (1
0)

8 (0
1)

39 (0
3)

196 (1
5)

24 (0
2)

53 (0
4)

134 (1
1) 177 (1
4)

65 (0
5)

0
09  0
4

219 (2
7)

26 (0
3) 124 (1
5)

38 (0
3) 212 (1
9) 303 (2
7)

57 (0
7)

175 (2
2)

27 (0
3) 194 (2
4)

123 (1
5) 125 (1
5)

168 (2
1)

73 (0
9)

9 (0
1)

14 (0
2)

84 (1
0)

14 (0
2)

24 (0
3)

59 (0
7) 94 (1
2)

34 (0
4)

0
08  0
4

4214 (52
0) 2
5  1
3

3882 (48
0)

8096 41
3  14
8

No depression

83 (0
7)

300 (2
6)

30 (0
3) 299 (2
6)

198 (1
7) 191 (1
7)

263 (2
3)

119 (1
1)

13 (0
1)

20 (0
2)

135 (1
2)

18 (0
2)

34 (0
3)

91 (0
8) 147 (1
3)

52 (0
5)

0
09  0
5

5876 (51
7) 5481 (48
3) 2
5  1
3

7550 (59
0)

11 357 41
8  15
0

Total

5238 (41
0) 2
4  1
3

12 788 46
1  16
8

Depression

Severe psoriasis

(continued)

84 (2
6)

12 (0
4) 88 (2
7)

26 (0
8)

125 (3
8)

3 (0
1) 105 (3
2)

75 (2
3) 66 (2
0)

95 (2
9)

46 (1
4)

4 (0
1)

6 (0
2)

51 (1
6)

4 (0
1)

10 (0
3)

32 (1
0) 53 (1
6)

18 (0
6)

0
11  0
5

1267 (38
9) 2
4  1
2

1994 (61
1)

3261 43
1  15
5

Depression

474 Psoriasis, depression and risk of atrial fibrillation and stroke, A. Egeberg et al.

© 2015 British Association of Dermatologists

© 2015 British Association of Dermatologists

antagonists

COPD, chronic obstructive pulmonary disease; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-2 receptor blocker. Values are n (%) unless stated otherwise.

126 (3
9) 5 (0
2) 167 (2
1) 17 (0
2) 1921 (2
8) 142 (0
2) Thiazide diuretics Vitamin K

122 781 (2
4) 11 307 (0
2)

1231 (2
4) 92 (0
2)

690 (4
3) 50 (0
3)

1628 (2
9) 120 (0
2)

1064 (2
4) 75 (0
2)

564 (4
4) 45 (0
4)

293 (2
6) 22 (0
2)

9 (0
3)

123 (3
8)

19 (0
2)

236 (2
9)

28 (0
3)

359 (3
2)

41 (0
3)

345 (2
7) 670 (1
5)

78 (0
2) 119 (0
2)

1015 (1
8) 468 (2
9)

50 (0
3) 97 (0
2)

906 (1
8)

147 (0
2)

1374 (2
0) 79 070 (1
5)

Total Total Total population

12 923 (0
3)

Systemic glucocorticoids

Spironolactone

Table 1 (continued)

Reference

Overall psoriasis

No depression

Depression

Mild psoriasis

No depression

Depression

Severe psoriasis

No depression

Depression

Psoriasis, depression and risk of atrial fibrillation and stroke, A. Egeberg et al. 475

developed AF, and 161 932 individuals were diagnosed with stroke, including 1262 cases of AF and 791 cases of stroke in patients with psoriasis without depression, and 403 cases of AF and 358 cases of stroke in patients with both psoriasis and depression. In all analyses, HRs for AF and stroke were consistently higher in patients with psoriasis with depression than in patients with psoriasis without depression. A higher risk of AF and stroke was also observed in patients with severe psoriasis compared with patients with mild psoriasis (Tables 2 and 3). The overall risk in patients with depression, regardless of psoriasis status, yielded fully adjusted HRs of 1
06 (95% CI 1
04–1
07, P < 0
001) for AF and 1
33 (95% CI 1
31–1
36, P < 0
001) for stroke. Atrial fibrillation The incidence rates per 1000 person-years for AF were 3
21 in the reference population and 5
58 in the overall psoriasis population. Stratified by severity of psoriasis, the incidence rates were 5
51 and 5
97 for patients with mild and severe psoriasis, respectively. Stratified by depression status, the overall incidence rates were 5
07 and 8
14 in patients with psoriasis without and with depression, respectively. Similarly, the incidence rates were 5
02, 8
41, 5
39 and 7
41 for patients with mild psoriasis without depression, mild psoriasis with depression, severe psoriasis without depression and severe psoriasis with depression, respectively. Compared with the reference population, the fully adjusted HRs for risk of AF were 1
14 (95% CI 1
08–1
33), 1
19 (95% CI 1
06–1
33), 1
32 (95% CI 1
15–1
53) and 1
74 (95% CI 1.43–2
11) in patients with mild psoriasis without depression, mild psoriasis with depression, severe psoriasis without depression, and severe psoriasis with depression, respectively (Fig. 2; Table 3). In the sensitivity analyses, the results were generally similar to the main analyses. Indeed, for patients with mild psoriasis without depression, HRs for AF ranged from 1
08 to 1
16 (all P < 0
05). HRs for patients with mild psoriasis with depression ranged from 1
17 to 1
33 (all P < 0
05), except for analysis D as described above (HR 1
33, 95% CI 0
95–1
85; P = 0
092). In patients with severe psoriasis without depression, HRs ranged from 1
19 to 1
34 (all P < 0
001), except for analysis A (HR 1
19, 95% CI 0
98–1
44; P = 0
076). In the sensitivity analyses of patients with severe psoriasis with depression, HRs ranged from 1
49 to 1
73 (all P < 0
05). Stroke There were higher rates of stroke in patients with severe psoriasis than in the reference population and in patients with mild psoriasis. The incidence rates per 1000 person-years were 2
62 and 3
84 for the reference population and for all patients with psoriasis, respectively. Classified by psoriasis severity and depression status, the incidence rates were 3
60 (mild psoriasis overall), 5
15 (severe psoriasis overall), 3
09 British Journal of Dermatology (2015) 173, pp471–479

237 35 304 6
71 5
91–7
62

244 47 389 5
15 4
54–5
84

123 33 991 3
62 3
03–4
32

121 13 398 9
03 7
56–10
79

(mild psoriasis without depression), 6
71 (mild psoriasis with depression), 3
62 (severe psoriasis without depression) and 9
03 (severe psoriasis with depression). The age-and sex-adjusted HRs for stroke were 1
72 (95% CI 1
51–1
95) and 2
72 (95% CI 2
28–3
25) for patients with mild psoriasis and depression, and patients with severe psoriasis and depression, respectively. The fully adjusted HRs changed marginally for both mild psoriasis with depression (HR 1
63, 95% CI 1
43–1
85) and severe psoriasis with depression (HR 2
47, 95% CI 2
07–2
95). The fully adjusted HRs did not show any increased risk of stroke in patients with mild psoriasis without depression, or severe psoriasis without depression, with HRs for mild psoriasis without depression, and severe psoriasis without depression of 0
95 (95% CI 0
88–1
03, P = 0
20) and 1
16 (95% CI 0
97–1
39, P = 0
095), respectively. All results for patients with concomitant depression remained statistically significant in the fully adjusted sensitivity analyses, and HRs ranged from 1
52 to 1
65 (mild psoriasis with depression) and from 2
18 to 2
64 (severe psoriasis with depression). Patients with mild psoriasis without depression did not show any increased risk of stroke in the sensitivity analyses (HRs between 0
91 and 0
96), except when applying hospital diagnoses (analysis D) for classification of depression (consequent HR 1
11, 95% CI 1
06–1
17). Patients with severe psoriasis without depression showed HRs between 1
15 and 1
44, albeit the HR was not statistically significant when excluding patients who used vitamin K antagonists (analysis B, P = 0
11).

905 251 652 3
60 3
37–3
84

Discussion

British Journal of Dermatology (2015) 173, pp471–479

CI, confidence interval.

1149 299 041 3
84 3
63–4
07 160 487 61 256 669 2
62 2
61–2
63

791 250 338 3
16 2
95–3
39

358 48 702 7
35 6
63–8
15

668 216 347 3
09 2
86–3
33

101 13 633 7
41 6
10–9
00 182 33 749 5
39 4
66–6
24 283 47 382 5
97 5
32–6
71 302 35 901 8
41 7
51–9
42 1382 250 928 5
51 5
22–5
81 1665 298 310 5
58 5
32–5
86 196 054 61 160 100 3
21 3
19–3
22

1262 248 776 5
07 4
80–5
36

403 49 534 8
14 7
38–8
97

1080 215 027 5
02 4
73–5
33

3261 8096 11 357 12 788 56 496 67 853

Total number Atrial fibrillation Number of events Person-years Incidence rate 95% CI Stroke Number of events Person-years Incidence rate 95% CI

5 184 035

51 804

16 049

43 708

Total Total Reference population

Total

No depression

Depression

No depression

Depression

Severe psoriasis Mild psoriasis Overall psoriasis

Table 2 Incidence rates of atrial fibrillation and stroke per 1000 person-years in patients with psoriasis with or without depression compared with the reference population

No depression

Depression

476 Psoriasis, depression and risk of atrial fibrillation and stroke, A. Egeberg et al.

In this nationwide cohort study, we found an increased risk of AF and stroke in patients with psoriasis with concurrent depression. Furthermore, we found an increased risk of AF, but not stroke, in patients with psoriasis without depression. The results were supported by sensitivity analyses, which showed increased risk of AF in patients with both mild and severe psoriasis, but with a higher risk in patients with concurrent depression. We also found a significantly increased risk of stroke in patients with both mild psoriasis with depression and severe psoriasis with depression. While the influence of depression has not been investigated before in this setting, we previously examined the risk of AF and ischaemic stroke in patients with psoriasis in a Danish nationwide cohort from 1997 to 2006, and found comparable results with those observed in the present study (Table 2, ‘overall psoriasis’), where follow-up was extended to 31 December 2011.3 The present results expand this finding to a substantially larger cohort, and in support of these results, increased risk of AF in patients with psoriasis was also very recently reported in hypertensive patients with left ventricular hypertrophy participating in the Losartan Intervention For Endpoint study.22 On the other hand, a subsequent single-centre US study found no increased risk of AF in patients with psoriasis, possibly reflecting that these patients were older © 2015 British Association of Dermatologists

Psoriasis, depression and risk of atrial fibrillation and stroke, A. Egeberg et al. 477 Table 3 Hazard ratios of atrial fibrillation and stroke in patients with psoriasis with or without depression Atrial fibrillation Hazard ratio

Stroke 95% CI

P-value

Crude estimates Overall psoriasis No depression 1
29 1
22–1
36 < 0
001 Depression 1
69 1
53–1
87 < 0
001 Mild psoriasis No depression 1
31 1
23–1
39 < 0
001 Depression 1
72 1
53–1
92 < 0
001 Severe psoriasis No depression 1
25 1
08–1
45 < 0
001 Depression 1
88 1
54–2
28 < 0
001 Adjusted for age and sex Overall psoriasis No depression 1
19 1
12–1
25 < 0
001 Depression 1
40 1
27–1
55 < 0
001 Mild psoriasis No depression 1
15 1
09–1
22 < 0
001 Depression 1
35 1
20–1
51 < 0
001 Severe psoriasis No depression 1
36 1
18–1
57 < 0
001 Depression 1
86 1
53–2
27 < 0
001 Adjusted for age, sex, comorbidities, medication and socioeconomic status Overall psoriasis No depression 1
17 1
11–1
24 < 0
001 Depression 1
24 1
12–1
38 < 0
001 Mild psoriasis No depression 1
14 1
08–1
33 < 0
001 Depression 1
19 1
06–1
33 < 0
05 Severe psoriasis No depression 1
32 1
15–1
53 < 0
001 Depression 1
74 1
43–2
11 < 0
001

Hazard ratio

95% CI

P-value

1
07 2
26

1
00–1
15 2
02–2
52

< 0
05 < 0
001

1
07 2
33

0
99–1
15 2
05–2
65

0
085 < 0
001

1
14 2
61

0
96–1
37 2
18–3
11

0
14 < 0
001

0
99 1
82

0
92–1
06 1
62–2
03

0
68 < 0
001

0
95 1
72

0
88–1
02 1
51–1
95

0
19 50 years) than our cohort, as age is an important risk factor for AF.23 In our current study, we found a consistent dose–response relationship between psoriasis severity and risk of AF, as well as an increased risk of AF independent of age, sex, socioeconomic status, comorbidities and use of concomitant medication. Our novel results with stratification by depression status suggest that depression is associated with an incremental increase in the risk of AF associated with psoriasis, and an important finding in our study was that during the median 5
1 years of follow-up, the risk of stroke in patients with psoriasis was increased only in patients with concurrent depression. This observation clearly suggests that depression may have a significant contributory role in the development of stroke in patients with psoriasis. The mechanism underlying this association requires further study, but systemic inflammation occurs in psoriasis, depression and AF, and it is tempting to speculate that the incremental contribution of depression to inflammation in patients with psoriasis and AF may be an important determinant of stroke risk in these patients. Also, both psoriasis and depression are independently associated © 2015 British Association of Dermatologists

with increased arterial stiffness, which is a risk factor for AF.24–26 Furthermore, our results suggest that the excess risk of AF in patients with psoriasis with (HR 1
24) vs. without (HR 1
17) depression was comparable with the effect of depression on the risk of AF in patients without psoriasis. Previously it has been discussed whether psoriasis is an independent risk factor for cardiovascular disease, and the sum of evidence supports this notion.2,4 However, in potential support of our findings, Wakkee et al.27 examined a large population-based cohort, and reported that psoriasis in itself was not a clinically relevant risk factor for ischaemic heart disease, and that depression, altered lifestyles and impaired health-related quality of life might affect the cardiovascular risk profile of patients with psoriasis. It is generally accepted that patients with depression have an increased risk of stroke.28,29 In addition to the contribution of inflammation, factors such as activation of the sympathetic nervous system, increased platelet activation and others (e.g. increased smoking, physical inactivity, obesity, comorbidities, lack of medication compliance and poorer diet) in patients with depression may be among mechanisms underlying the British Journal of Dermatology (2015) 173, pp471–479

478 Psoriasis, depression and risk of atrial fibrillation and stroke, A. Egeberg et al.

Fig 2. Forest plot of fully adjusted hazard ratios for atrial fibrillation and stroke in patients with psoriasis with or without depression.

association between depression and stroke.28,30,31 In support of the importance of inflammation, epidemiological studies of other inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease, have also found a dose–response relationship between disease severity and the risk of stroke.32,33 On the other hand, it is unclear whether use of antidepressants can modify the risk of AF and stroke in patients with depression.34,35 However, studies have suggested that the inflammatory cytokine balance in depression may be favourably altered by treatment with antidepressants, and a recent report found that use of serotonin reuptake inhibitors in patients with psoriasis was associated with decreased need for systemic psoriasis treatment.36–39 Moreover, the relationship between depression and inflammation is substantiated by the intriguing observation that biological treatment, for example with TNF-a inhibitors, can reduce depressive symptoms in patients with psoriasis.40,41 The high accuracy of the Danish registries, as well as the available information on socioeconomic status, medication and comorbidities, allows for large-scale nationwide analyses, in which selection and recall bias are minimized. As the results of our sensitivity analyses were generally in accordance with those of our primary analysis, the risk of bias due to misclassification of patients with psoriasis or depression is likely to be low. We did not have comprehensive data on the use of biologics throughout the entire study period. However, as patients with mild psoriasis with depression had a higher risk of stroke than patients with mild British Journal of Dermatology (2015) 173, pp471–479

psoriasis without depression, and as biologics are used exclusively in patients with moderate-to-severe psoriasis in Denmark, exposure to biologics is unlikely to have markedly confounded our results. In the present study, the median follow-up time from the onset of psoriasis was 5
1 years, and we acknowledge that long-term sequelae of psoriasis such as stroke might occur much later on and hence be underestimated in the current report. While the registries used in this study allow for detailed information on a wide variety of comorbid conditions, information on certain risk factors for cardiovascular disease (e.g. blood pressure, smoking, alcohol consumption, exercise habits and body mass index) was not available, although we attempted to adjust for these risk factors by use of surrogates, for example antihypertensive medication and cholesterol-lowering medication as surrogates for hypertension and hypercholesterolaemia, respectively. In conclusion, depression was associated with an incremental increase in the risk of AF in patients with psoriasis. Given the differences observed across severities of psoriasis and between psoriasis with and without concomitant depression, each patient subgroup should be taken into consideration in clinical practice and future research.

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British Journal of Dermatology (2015) 173, pp471–479