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DOI: 10.1111/jdv.12909
REVIEW ARTICLE
Effect of biologics on depressive symptoms in patients with psoriasis: a systematic review P. Fleming,1,* C. Roubille,2 V. Richer,3 T. Starnino,4 C. McCourt,5 A. McFarlane,6 S. Siu,7 J. Kraft,8 C. Lynde,8 J.E. Pope,7 S. Keeling,6 J. Dutz,5 L. Bessette,9 R. Bissonnette,10 B. Haraoui,11 W.P. Gulliver12 1
Division of Dermatology, University of Toronto, Toronto, ON, Canada Notre-Dame Hospital, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC, Canada 3 Department of Medicine, Dermatology Service, St-Luc Hospital, Montreal, Canada 4 Sacr e-Coeur Hospital of Montreal, University of Montreal, Montreal, QC, Canada 5 Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada 6 Division of Rheumatology, University of Alberta, Edmonton, AB, Canada 7 Division of Rheumatology, Department of Medicine, Western University, St. Joseph’s Health Care, London, ON, Canada 8 Lynde Dermatology, Markham, ON, Canada 9 bec (pavillon CHUL), Quebec City, QC, Department of Medicine, Rheumatic Disease Unit, Centre Hospitalier Universitaire de Que Canada 10 Innovaderm Research, Montreal, QC, Canada 11 de Montre al (CHUM) and Institut de Department of Medicine, Rheumatic Disease Unit, Centre Hospitalier de l’Universite al, Montreal, QC, Canada Rhumatologie de Montre 12 Department of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada *Correspondence: P. Fleming. E-mail: fl[email protected] 2
Abstract Background Twenty to fifty percent of patients with psoriasis have depressive symptoms. Objective To describe the effects of biologics (tumour necrosis factor inhibitors [TNFi] or interleukin 12/23 inhibitors [IL-12/23i]) on depressive symptoms in patients with psoriasis. Methods Electronic databases were searched for randomized controlled trials (RCTs) examining the effects of biologics on depressive symptoms in adults with psoriasis. Results Of the 305 publications identified, three RCTs were included in a systematic review. In a trial evaluating ustekinumab, mean change in Hospital and Anxiety Depression Rating Scale at 24 weeks from baseline was 3.1 with ustekinumab (P < 0.001) vs. 0.21 with placebo (not significant). In a trial evaluating adalimumab, mean change in Zung Self-Rating Depression Scale at 12 weeks from baseline was
6.7 with adalimumab vs.
1.5 with placebo. In a trial eval-
uating etanercept, the between-group difference at 12 weeks in Beck Depression Inventory Scale was 1.8 (95% CI: 0.6, 2.90) in favour of etanercept over placebo. Limitations are that diagnostic criteria for depression were not used and scales and data from individual RCTs could not be combined. Conclusion Adalimumab, etanercept and ustekinumab were associated with statistically significant reductions in depressive symptom scores using various scales in patients with moderate-to-severe psoriasis. Received: 1 September 2014; Accepted: 5 November 2014
Conflicts of interest PF, CR, VR, TS, CM and SS have no conflict of interest relevant to this article to declare; AM owns stock in Pfizer; JK has acted as consultant, advisor and/or speaker for AbbVie, Amgen, Janssen, Leo Pharma and Novartis; CL has acted as a principal investigator, speaker and/or consultant for AbbVie, Amgen, Celgene, Eli Lilly, Galderma, Janssen, Leo Pharma, Merck, Novartis, Pfizer and Valeant; JP has received research grants and/or has been a consultant for AbbVie, Actelion, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Pfizer, Roche and UCB; SK has received unrestricted educational grants and consultancy fees from AbbVie, Amgen, AstraZeneca, Janssen, Roche and UCB; JD has received honoraria for participation in advisory boards and as a speaker for AbbVie, Amgen, Janssen and Leo Pharma; LB has received consulting fees, research grants, and honoraria for participation as a speaker for AbbVie, Amgen, Bristol-Myers Squibb, Janssen, Pfizer, Roche, Sanofi and UCB; RB has received honoraria for participation in advisory boards and/or research grants from AbbVie, Amgen, Celgene, Eli Lilly Galderma, Incyte, Janssen, Leo Pharma, Merck, Novartis, Pfizer and Tribute; BH has received honoraria for participation in advisory boards and/or research grants from AbbVie, Amgen,
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Bristol-Myers Squibb, Janssen, Pfizer, Roche and UCB; WPG has received honoraria for participation in advisory boards for AbbVie, Amgen, Bio-K and Janssen and for participation in speaker engagements and consultative meetings for AbbVie, Actelion, Amgen, Janssen, Leo Pharma, Novartis and Roche.
Funding sources This publication summarizes the results of the Canadian Dermatology-Rheumatology (DR) Co-morbidity Initiative systematic literature searches (MEDLINE, EMBASE, Cochrane Library, 2010–2012 ACR, EULAR, AAD, EADV abstracts) and consensus-based recommendations from a meeting on the management of comorbidities, held in Toronto, Canada on 31 May to 1 June 2013, which was sponsored by AbbVie. AbbVie provided funding to Pinnacle Marketing & Education Inc., 7 Daoust, Hudson, QC, Canada, to manage the Canadian DR Co-morbidity Initiative that led to this paper. AbbVie paid consultancy fees to BH, JP, LB, SK, RB, WG, JD, CL and JK for their participation in the Canadian DR Co-morbidity Initiative. Travel to and from the meeting was reimbursed. AbbVie provided suggestions for topic ideas for the Canadian DR Co-morbidity Initiative and proposed authors for this study. AbbVie attended the meeting, but was not involved in the development of the study. AbbVie did have the opportunity to review the final version of the publication. This publication reflects the opinions of the authors. PF prepared a draft outline for co-authors’ comment and approval. Each author reviewed the publication at all stages of development to ensure that it accurately reflects the results of their literature searches and the consensus-based recommendations from the meeting experts. The authors determined final content, and all authors read and approved the final publication. The authors maintained complete control over the content of the study. No payments were made to the authors for the writing of this publication. Juliette Allport of Leading Edge (part of the Lucid Group), Burleighfield House, Buckinghamshire, UK subsequently supported incorporation of comments into final drafts for author approval, and editorial styling required by the journal. AbbVie paid Leading Edge for this work. CR received a fellowship grant/bursary from the Foundation of the University of Montreal Hospital Center (CHUM).
Introduction Psoriasis is a common chronic immune-mediated inflammatory disorder affecting 2–3% of the population.1 There are several significant comorbidities associated with this systemic illness including cardiovascular disease, inflammatory bowel disease and psoriatic arthritis.1,2 Clinical observation is also suggestive of comorbid depression among patients afflicted with skin diseases, with some studies estimating that around one-quarter of patients in dermatology practices have a psychiatric disorder.3,4 Several observational studies have assessed the rate of depression or depressive symptoms among patients with psoriasis. In a case–control study performed in a dermatology clinic,5 Akay and colleagues found a significantly higher prevalence of depressive symptoms (evaluated according to the Beck Depression Inventory [BDI]) in patients with psoriasis than healthy controls (58% vs. 20%, P < 0.01). In another case– control study,6 mean BDI-II score was significantly higher in participants with psoriasis compared with healthy controls (16.04 vs. 5.75, P < 0.001, BDI-II ≥13 is suggestive of depression). The prevalence of depression (assessed with the Center for Epidemiological Study Depression Scale) in patients with self-reported psoriasis was 48.7% in a cross-sectional study performed in the United States.7 Furthermore, a large population-based cohort study using data from the United Kingdom General Practice Research Database found that the risk of depression was significantly elevated in patients with psoriasis compared with controls (adjusted hazard ratio: 1.39; 95% CI:
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1.37, 1.41).8 A diagnosis of psoriatic arthritis may further increase the likelihood of depression, with a quasi-experimental study in 618 participants reporting that patients with psoriatic arthritis had a higher prevalence of depression (32.4%; 95% CI: 23.7, 41.1) than those with psoriasis alone (20.7%: 95% CI 15.1, 26.3).9 Similar to psoriasis, depression is a chronic disorder with significant morbidity and mortality. Depression has long thought to be caused by a combination of psychosocial and biological factors. In particular, monoamine dysfunction is considered key the pathophysiology of this disease. Recent evidence points towards interactions between the immune and central nervous systems playing a role in depression.10,11 It remains unclear if the elevated rate of depression among patients with psoriasis may be a primary disorder relating to cytokine dysregulation or a secondary disorder involving psychosocial factors. Therefore, it is important to understand the effect, if any, of current treatments on this comorbidity. Many psoriasis treatments, including topical corticosteroids, methotrexate and cyclosporine, target the immune system. An important driver of the immunopathogenesis of psoriasis includes upregulation of pro-inflammatory cytokines such as tumour necrosis factor (TNF), interleukin (IL)-12 and IL-23. These are attractive treatment targets and, accordingly, biologics such as TNF inhibitors (TNFi; adalimumab, etanercept, infliximab, golimumab and certolizumab) and IL-12/23 inhibitors (IL-12/23i; ustekinumab) have become important tools in
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Effects of biologics on depressive symptoms in psoriasis
the management of moderate-to-severe psoriasis. There is evidence suggestive of a benefit of TNFi in reducing cardiovascular disease, a common psoriatic comorbidity, in immune-mediated diseases such as psoriasis and rheumatoid arthritis.12–14 We were interested in any possible effects biologics may have on depression in patients with psoriasis. The primary objective of this systematic review was to describe the effect of biologics (TNFi and IL12/23i) on depressive symptoms (measured by validated depression rating scales) in adult patients with psoriasis. This is part of a larger project: the Canadian Dermatology-Rheumatology CoMorbidities Initiative. This group includes a panel of dermatologists, rheumatologists and residents based in Canada that has developed evidencebased recommendations on the management of comorbidities in dermatological and rheumatological diseases.15
3
Study screening
The titles and abstracts of articles were initially screened for inclusion by P.F. using our predetermined criteria (phase I). The full texts of selected articles were then independently assessed for inclusion in an unblinded fashion by P.F. and W.P.G. (phase II). Disagreement between the reviewers was resolved by consensus. Data extraction
Recommendations of the Preferred Items for the Reporting of Systematic Reviews Meta-Analysis (PRISMA) statement were followed as applicable.16
One reviewer (P.F.) extracted data and synthesized it in tabular format. Extracted data were triple checked for accuracy. We extracted data on study characteristics (design, participant age and sex, inclusion/exclusion criteria, sample size and study duration); comparator group (placebo or usual care); outcome measures (proportion of patients with depressive symptoms as defined by study investigators, depression assessment tool and mean score on depression rating scales); intervention type; method of analysis (intention-to-treat or per-protocol analysis); and study completion rate. The level of evidence for each included article was evaluated using the Oxford Center for Evidence-Based Medicine scale.18
Eligibility
Outcomes
We included randomized controlled trials (RCTs) that were performed in patients aged 18 years or older with a clinical or histological diagnosis of psoriasis and that used a standardized measure of depression (such as a depression rating scale). We included TNF-a inhibitors and IL-12/23 inhibitors currently approved for use in plaque psoriasis. We broadly defined depression to include the presence of ‘depressive symptoms’ as assessed by most rating scales. Because depressive symptoms can take weeks or months to resolve, we required studies to have a follow-up period of at least 12 weeks. In addition, studies must have used an intention-to-treat analysis. Study quality was assessed using the U.S. Preventive Services Task Force quality rating criteria for RCTs.17 Only studies considered ‘good’ or ‘fair’ according to these criteria were included. We excluded studies that failed to account for confounding effects of major systemic illness (e.g. recent myocardial infarction or malignancy) either by exclusion, adjustment or multivariate modelling.
Our primary outcome was a significant reduction in depression scores on depression rating scales. Our secondary outcome was a reduced proportion of depressed patients as measured by depression rating scales.
Methods
Search strategy
We searched PUBMED, EMBASE and the Cochrane Database for relevant studies performed in humans and published in English. No date limits were set. Search terms (MeSH headings) included psoriasis and depression or depressive symptoms. We hand-searched the reference lists of included articles for any additional relevant studies. We also searched the proceedings of the American Academy of Dermatology and European Academy of Dermatology and Venereology annual meetings from 2010 to 2012 to identify any potentially relevant abstracts.
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Risk of bias
We assessed the risk of bias in the selected RCTs by considering randomization sequence generation, allocation concealment, participant blinding, healthcare provider blinding, outcome assessor blinding and study attrition.16
Results We initially identified 305 articles in our literature search, of which four were eligible for inclusion in our analysis. Reasons for exclusion are shown in Fig. 1. All studies were of good quality and the level of evidence was 1b. All included adequate reporting of our key measures of bias and all used intention-totreat analysis. Of the included studies, three were RCTs19–21 that examined the effects of ustekinumab, adalimumab or etanercept, respectively, on depressive symptoms in patients with psoriasis. One additional study was an open-label extension of the etanercept-focused RCT.22 These studies had a combined sample size of 1946 patients. Study characteristics are presented in Table 1. No published RCTs were identified that evaluated the effects of infliximab, golimumab or certolizumab on depression or depressive symptoms in patients with psoriasis. Synthesis of results
All three RCTs demonstrated significant reductions in depression scores in patients treated with TNFi and IL12/23i with
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Figure 1 PRISMA flow diagram of study selection process.
12–24 weeks of follow-up19–21 (Table 2). Groups treated with ustekinumab and adalimumab demonstrated significant reductions in depression symptom scores at follow-up compared with baseline with no significant reduction in the placebo groups.19,20 In the trial comparing ustekinumab with placebo, there was a significantly lower proportion of people meeting the Hospital and Anxiety Depression Scale criteria for depression in the intervention group after 12 weeks (P < 0.001).19 In the study comparing etanercept with placebo, etanercept was associated with significantly greater improvements in both the BDI and Hamilton depression scores at 12 weeks.21 Although there was a nonsignificant between-group difference in the proportion of patients with depression at 12 weeks, the trend was towards a lower prevalence of depression in the etanercept group. In addition, in the open-label extension of this trial, such changes were sustained for up to 96 weeks in the case of etanercept.22
Discussion Depression is a common comorbidity in patients with psoriasis. A recent meta-analysis examining the rate of depression in psoriasis found a prevalence of 28% based on depression rating scales.23 When analysing studies with controls, the investigators found that patients with psoriasis were more likely to have depression than those without psoriasis (odds ratio [OR]: 1.57; 95% CI: 1.40, 1.76).
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Our systematic review continues the evaluation of this comorbidity in patients with psoriasis by examining the effect of psoriasis treatment on depressive symptoms. To our knowledge, this is the only systematic review on the use of biologics in patients with psoriasis and depression. Analysis of data from 1,946 participants indicates that TNFi and IL12/23i can significantly reduce depressive symptoms after 12–24 weeks of use in patients with moderate-to-severe psoriasis. There are several reasons why biologics may affect depressive symptoms in patients with psoriasis and depend on whether this comorbidity is a primary disorder relating to cytokine dysregulation or secondary disorder involving psychosocial factors. The immune system may play a role in the pathogenesis of depression. There is evidence that cytokines can not only access the central nervous system through blood–brain barrier transport proteins, but can also affect neuronal calcium regulation much like the monoamines implicated in depression.10,11,24,25 A recent meta-analysis examined levels of cytokines in patients meeting Diagnostic and Statistical Manual (DSM) criteria for major depression.25 The researchers found that levels of TNF-alpha were significantly elevated in patients with depression compared with controls without depression (weighted mean difference: 3.97; 95% CI: 2.24, 5.71). A placebo-controlled RCT evaluating infliximab in non-psoriatic patients with major depressive disorder found a significant reduction in depressive symptoms with
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Multicentre RCT in USA, Canada & Europe
Multicentre RCT in USA & Canada
Menter et al., 2010
Tyring et al., 2006
96
620
Inclusion: plaque psoriasis for >1 year, age > 18 years, BSA >5%, TNFi-na€ıve Exclusion: history of cancer, tuberculosis, neurological disease Inclusion: plaque psoriasis, age >18 years psoriasis, BSA >10%, prior systemic/phototherapy Exclusion: psychiatric disease, guttate/erythrodermic/pustular psoriasis, prior TNFi use, recent topical corticosteroids 464
1230
Inclusion: moderate-severe psoriasis, age >18 years, PASI >12, BSA >10%, candidate for systemic/phototherapy Exclusion: non-plaque psoriasis, serious systemic disease, malignancy, recent biologic use (3 months), recent systemic therapy (4 weeks), recent topical therapy (2 weeks), active tuberculosis
Inclusion: All patients who completed randomized controlled phase of trial (placebo and intervention)
Sample size (n)
Eligibility criteria
BSA, body surface area; PASI, Psoriasis Area Severity Index; SC, subcutaneous. *Based on trial data from Tyring et al.,21 included for discussion.
Open-label multicentre extension of study by Tyring et al.
Multicentre, cross-over RCT in USA, Canada & Europe
Langley et al., 2010
Krishnan et al., 2006*
Design
Study
Table 1 Characteristics of included clinical trials
Etanercept 50 mg SC twice weekly
Placebo
Not reported
45.6 (12.1)
45.8 (12.8)
43.3 Etanercept 50 mg SC twice weekly
Placebo
Not reported
70
65
65
70
69.0
47.0 (12.5)
Placebo
45.6
66.7
47.0 (12.1)
Ustekinumab 90 mg SC at weeks 0, 4, then q12 weeks Adalimumab 80 mg SC initial dose then 40 mg q2 weeks.
69.2
Male gender (%)
45.1 (12.1)
Mean age (years, SD)
Patient characteristics
Ustekinumab 45 mg SC at weeks 0, 4, then q12 weeks
Intervention
96
12
12
24
Follow-up duration (weeks)
Effects of biologics on depressive symptoms in psoriasis 5
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Good
Good
Good
Langley et al., 2010
Menter et al., 2010
Tyring et al., 2006 BDI-I (score >9 indicates depression) Ham-D (score >6 indicates depression)
ZDS (score >50 indicates depression)
HADS (score >9 indicates depression)
Depression rating tool
Mean change in depression score 1.7 (SD 3.1) vs. baseline (P < 0.001) 2.1 (SD 3.4) vs. baseline (P < 0.001) +0.21 (SD 2.8) vs. baseline (NS) 6.7 (95% CI: 10.1, 3.1) vs. baseline 1.5 (95% CI: 4.0, +1.0) vs. baseline BDI: 1.8 (95% CI: 0.6, 2.9) for etanercept vs. placebo Ham-D: 1.2 (95% CI: 0.4, 1.9) for etanercept vs. placebo
Prevalence of depression/ depressive symptoms (%) Baseline: 24.7 24 weeks: 12.8 (P < 0.001) Baseline: 31.1 24 weeks: 12.5 (P < 0.001) Baseline: 24.2 24 weeks: 26.7 (NS) Baseline: 32% 12 weeks: not reported Baseline: 37% 12 weeks: not reported Baseline: 34% 12 weeks: 16% (BDI) Baseline: 35% 12 weeks: 20% (BDI) (P = 0.16 for etanercept vs. placebo at week 12)
Intervention Ustekinumab 45 mg Ustekinumab 90 mg Placebo
Adalimumab
Placebo
Etanercept
Placebo
3.7
11.4
3.4
Lost to follow-up (%)
BDI, Beck Depression Inventory; HADS, Hospital and Anxiety Depression Rating Scale; Ham-D, Hamilton Rating Scale for Depression; ZDS, Zung Self-Rating Depression Scale. *U.S. Preventive Services Task Force quality rating criteria. †Oxford Center for Evidence-Based Medicine scale.
Study quality*
Study
Table 2 Outcome data on depression or depressive symptoms for included clinical trials
1b
1b
1b
Level of evidence†
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Effects of biologics on depressive symptoms in psoriasis
infliximab in those patients with higher baseline serum C-reactive protein and TNF levels, although there was no betweentreatment difference in change in depressive symptoms across the overall study population.26 Therefore, if depression in psoriasis is related to cytokine dysfunction (at least in part), then modifying circulating cytokine levels may affect depressive symptoms. An alternative explanation for the ability of biologics to reduce depressive scores relates to psychosocial factors such as improved quality of life and reduced social stigma with improved signs and symptoms of psoriasis. It is well established that psychosocial factors have a major impact on the course of both endogenous and reactive clinical depression. Likewise, there is strong evidence suggestive of the important role that psychological and social factors play in psoriasis. It has long been known that emotional stress can precipitate a flare of psoriasis27 and that patients with psoriasis can experience substantially reduced quality of life that may both impair social and occupational function. The quality of life among patients with psoriasis is comparable with many serious illnesses such as coronary disease and malignancy.28 Likewise, cutaneous illnesses can carry a high risk of stigma due to the visibility of skin lesions.29 The most likely explanation for the relationship between psoriasis and depression is multifactorial with a combination of genetic predisposition, cytokine dysfunction and psychosocial risk factors. Indeed, in the studies evaluated in this systematic review, quality of life, fatigue and Psoriasis Area Severity Index scores improved in parallel with depressive symptoms. Depression in patients with psoriasis may have substantial impact on more than just quality of life. Rheumatoid arthritis (RA) is another autoimmune disease with a high rate of depression.30 There is growing evidence of higher rates of mortality in depressed compared with non-depressed RA patients. Retrospective analysis of a cohort of 1290 RA patients found that the mortality risk increased with each additional unit on depression scale scores (OR: 1.35; 95% CI: 1.1,1.6).31 Likewise, another retrospective cohort analysis involving 22 131 patients with RA found a mortality risk among those with self-reported depression (hazard ratio: 1.3; P = 0.002).32 At present, there are no long-term mortality data on psoriasis patients with depression. However, given that patients with depression generally have higher all-cause mortality rates than the general population, it would not be unreasonable to assume this is the case in those with psoriasis as well. Given the high rates of concurrent illness, we propose several recommendations for management of depression in patients with psoriasis. We consider that it is reasonable to screen patients with psoriasis for depression when appropriate. The U.S. Preventive Services Task Force review on depression screening reported that asking two basic questions may be as effective at identifying patients with depression as more complex screening instruments.33 These include: ‘Over the past 2 weeks, have
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you felt down, depressed, or hopeless?’ and ‘Over the past 2 weeks, have you felt little interest or pleasure in doing things?’ A positive screen should initiative referral to an appropriate healthcare provider such as a family physician or psychiatrist. The three RCTs evaluated in this systematic review suggest a beneficial effect of TNFi and IL12/23i on depressive symptoms in patients with moderate-to-severe psoriasis. Further clinical trials that include prevalence of depression or change in depressive symptoms as primary endpoints and involve standardized psychiatric interviews are required to better understand the effect of biologics on depression in patients with psoriasis before recommendations on their use can be formulated. This systematic review has several limitations. Firstly, none of the included studies used DSM criteria to diagnose major depression. The scales and data from individual RCTs could not be combined. Depression rating scales are useful in measuring the severity of symptoms in depressed patients but they cannot replace a psychiatric interview as a diagnostic tool. Furthermore, the depression rating scales utilized in the included studies have several flaws that may affect their validity in detecting true depression. Many items on these scales include somatic symptoms resulting in ‘criterion contamination’.34 For example, the BDI has questions such as, ‘I can sleep as well as usual’ or ‘I am no more worried about my health than usual’. It is conceivable that patients with psoriasis without depression may have poorer sleep due to pruritus or they may worry about their health more than patients without psoriasis, thereby interfering with their true scores. It is not clear what relation, if any, these items have with true major depressive disorder. In addition, concomitant use of antidepressants during the interventions was not consistently reported in the studies so any potential confounding effect cannot be accounted for in this review. Therefore, the publications used in this analysis cannot be used to assess the effect of biologics on depression, but can only be used in an assessment of the effect of biologics on depressive symptoms in patients with scores suggestive of clinical depression. An additional limitation of this review is the lack of published evidence on the effect of other immune-modifying treatments such as methotrexate or cyclosporine on depressive symptoms. Given that these agents can also lower TNF levels, such treatments may be beneficial in patients with psoriasis and depression. In conclusion, three high-quality RCTs have demonstrated a reduction in depression scores on common depression rating scales after 12–24 weeks of TNFi or IL12/23i treatment in patients with psoriasis. While such scales used in conjunction with signs and symptoms are suggestive of major depressive disorder, a robust RCT including standardized DSM psychiatric interviews is required to better determine the clinical significance of these findings. In the interim, it is reasonable to screen patients with psoriasis for depression when appropriate and refer accordingly.
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Acknowledgements We would like to acknowledge Dr. Terrence Callanan, Professor of Psychiatry at Memorial University of Newfoundland, St. John’s, Newfoundland, Canada for providing advice on this manuscript.
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17 U.S. Preventive Services Task Force. U.S. Preventive Services Task Force procedure manual. Appendix VII. AHRQ Publication No. 08-05118-EF. [WWW document] July 2008. Available at http://www.uspreventiveservicestaskforce.org/uspstf08/methods/procmanualap7.htm (last accessed: 25 February 2013). 18 Howick J, Chalmers I, Glasziou P et al. Oxford levels of evidence 2. Oxford Centre for Evidence-Based Medicine. URL http://www.cebm.net/ index.aspx?o = 5653 (last accessed: 1 March 2013). 19 Langley RG, Feldman SR, Han C et al. Ustekinumab significantly improves symptoms of anxiety, depression, and skin-related quality of life in patients with moderate-to-severe psoriasis: results from a randomized, double-blind, placebo-controlled phase III trial. J Am Acad Dermatol 2010; 63: 457–465. 20 Menter A, Augustin M, Signorovitch J et al. The effect of adalimumab on reducing depression symptoms in patients with moderate to severe psoriasis: a randomized clinical trial. J Am Acad Dermatol 2010; 62: 812–818. 21 Tyring S, Gottlieb A, Papp K et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet 2006; 367: 29–35. 22 Krishnan R, Cella D, Leonardi C et al. Effects of etanercept therapy on fatigue and symptoms of depression in subjects treated for moderate to severe plaque psoriasis for up to 96 weeks. Br J Dermatol 2007; 157: 1275–1277. 23 Dowlatshahi EA, Wakkee M, Arends LR, Nijsten T. The prevalence and odds of depressive symptoms and clinical depression in psoriasis patients: a systematic review and meta-analysis. J Invest Dermatol 2013; 134: 1542– 1551. 24 Miller AH, Haroon E, Raison CL, Felger JC. Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depress Anxiety 2013; 30: 297–306. 25 Dowlati Y, Herrmann N, Swardfager W et al. A meta-analysis of cytokines in major depression. Biol Psychiatry 2010; 67: 446–457. 26 Raison CL, Rutherford RE, Woolwine BJ et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatmentresistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry 2013; 70: 31–41. 27 Seville RH. Psoriasis and stress. Br J Dermatol 1977; 97: 297–302. 28 Rapp SR, Feldman SR, Exum ML, Fleischer AB Jr, Reboussin DM. Psoriasis causes as much disability as other major medical diseases. J Am Acad Dermatol 1999; 41(3 Pt 1): 401–407. 29 Schmid-Ott G, Jaeger B, Kuensebeck HW, Ott R, Lamprecht F. Dimensions of stigmatization in patients with psoriasis in a “Questionnaire on Experience with Skin Complaints”. Dermatology 1996; 193: 304–310. 30 Dickens C, McGowan L, Clark-Carter D, Creed F. Depression in rheumatoid arthritis: a systematic review of the literature with meta-analysis. Psychosom Med 2002; 64: 52–60. 31 Ang DC, Choi H, Kroenke K, Wolfe F. Comorbid depression is an independent risk factor for mortality in patients with rheumatoid arthritis. J Rheumatol 2005; 32: 1013–1019. 32 Wolfe F, Michaud K. Predicting depression in rheumatoid arthritis: the signal importance of pain extent and fatigue, and comorbidity. Arthritis Rheum 2009; 61: 667–673. 33 Preventive US. Services Task Force. Screening for depression in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2009; 151: 784–792. 34 Pincus T, Hassett AL, Callahan LF. Criterion contamination of depression scales in patients with rheumatoid arthritis: the need for interpretation of patient questionnaires (as all clinical measures) in the context of all information about the patient. Rheum Dis Clin North Am 2009; 35(4): 861– 864, xi–xii.
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DOI: 10.1111/jdv.12909
REVIEW ARTICLE
Effect of biologics on depressive symptoms in patients with psoriasis: a systematic review P. Fleming,1,* C. Roubille,2 V. Richer,3 T. Starnino,4 C. McCourt,5 A. McFarlane,6 S. Siu,7 J. Kraft,8 C. Lynde,8 J.E. Pope,7 S. Keeling,6 J. Dutz,5 L. Bessette,9 R. Bissonnette,10 B. Haraoui,11 W.P. Gulliver12 1
Division of Dermatology, University of Toronto, Toronto, ON, Canada Notre-Dame Hospital, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC, Canada 3 Department of Medicine, Dermatology Service, St-Luc Hospital, Montreal, Canada 4 Sacr e-Coeur Hospital of Montreal, University of Montreal, Montreal, QC, Canada 5 Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada 6 Division of Rheumatology, University of Alberta, Edmonton, AB, Canada 7 Division of Rheumatology, Department of Medicine, Western University, St. Joseph’s Health Care, London, ON, Canada 8 Lynde Dermatology, Markham, ON, Canada 9 bec (pavillon CHUL), Quebec City, QC, Department of Medicine, Rheumatic Disease Unit, Centre Hospitalier Universitaire de Que Canada 10 Innovaderm Research, Montreal, QC, Canada 11 de Montre al (CHUM) and Institut de Department of Medicine, Rheumatic Disease Unit, Centre Hospitalier de l’Universite al, Montreal, QC, Canada Rhumatologie de Montre 12 Department of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada *Correspondence: P. Fleming. E-mail: fl[email protected] 2
Abstract Background Twenty to fifty percent of patients with psoriasis have depressive symptoms. Objective To describe the effects of biologics (tumour necrosis factor inhibitors [TNFi] or interleukin 12/23 inhibitors [IL-12/23i]) on depressive symptoms in patients with psoriasis. Methods Electronic databases were searched for randomized controlled trials (RCTs) examining the effects of biologics on depressive symptoms in adults with psoriasis. Results Of the 305 publications identified, three RCTs were included in a systematic review. In a trial evaluating ustekinumab, mean change in Hospital and Anxiety Depression Rating Scale at 24 weeks from baseline was 3.1 with ustekinumab (P < 0.001) vs. 0.21 with placebo (not significant). In a trial evaluating adalimumab, mean change in Zung Self-Rating Depression Scale at 12 weeks from baseline was
6.7 with adalimumab vs.
1.5 with placebo. In a trial eval-
uating etanercept, the between-group difference at 12 weeks in Beck Depression Inventory Scale was 1.8 (95% CI: 0.6, 2.90) in favour of etanercept over placebo. Limitations are that diagnostic criteria for depression were not used and scales and data from individual RCTs could not be combined. Conclusion Adalimumab, etanercept and ustekinumab were associated with statistically significant reductions in depressive symptom scores using various scales in patients with moderate-to-severe psoriasis. Received: 1 September 2014; Accepted: 5 November 2014
Conflicts of interest PF, CR, VR, TS, CM and SS have no conflict of interest relevant to this article to declare; AM owns stock in Pfizer; JK has acted as consultant, advisor and/or speaker for AbbVie, Amgen, Janssen, Leo Pharma and Novartis; CL has acted as a principal investigator, speaker and/or consultant for AbbVie, Amgen, Celgene, Eli Lilly, Galderma, Janssen, Leo Pharma, Merck, Novartis, Pfizer and Valeant; JP has received research grants and/or has been a consultant for AbbVie, Actelion, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Pfizer, Roche and UCB; SK has received unrestricted educational grants and consultancy fees from AbbVie, Amgen, AstraZeneca, Janssen, Roche and UCB; JD has received honoraria for participation in advisory boards and as a speaker for AbbVie, Amgen, Janssen and Leo Pharma; LB has received consulting fees, research grants, and honoraria for participation as a speaker for AbbVie, Amgen, Bristol-Myers Squibb, Janssen, Pfizer, Roche, Sanofi and UCB; RB has received honoraria for participation in advisory boards and/or research grants from AbbVie, Amgen, Celgene, Eli Lilly Galderma, Incyte, Janssen, Leo Pharma, Merck, Novartis, Pfizer and Tribute; BH has received honoraria for participation in advisory boards and/or research grants from AbbVie, Amgen,
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Bristol-Myers Squibb, Janssen, Pfizer, Roche and UCB; WPG has received honoraria for participation in advisory boards for AbbVie, Amgen, Bio-K and Janssen and for participation in speaker engagements and consultative meetings for AbbVie, Actelion, Amgen, Janssen, Leo Pharma, Novartis and Roche.
Funding sources This publication summarizes the results of the Canadian Dermatology-Rheumatology (DR) Co-morbidity Initiative systematic literature searches (MEDLINE, EMBASE, Cochrane Library, 2010–2012 ACR, EULAR, AAD, EADV abstracts) and consensus-based recommendations from a meeting on the management of comorbidities, held in Toronto, Canada on 31 May to 1 June 2013, which was sponsored by AbbVie. AbbVie provided funding to Pinnacle Marketing & Education Inc., 7 Daoust, Hudson, QC, Canada, to manage the Canadian DR Co-morbidity Initiative that led to this paper. AbbVie paid consultancy fees to BH, JP, LB, SK, RB, WG, JD, CL and JK for their participation in the Canadian DR Co-morbidity Initiative. Travel to and from the meeting was reimbursed. AbbVie provided suggestions for topic ideas for the Canadian DR Co-morbidity Initiative and proposed authors for this study. AbbVie attended the meeting, but was not involved in the development of the study. AbbVie did have the opportunity to review the final version of the publication. This publication reflects the opinions of the authors. PF prepared a draft outline for co-authors’ comment and approval. Each author reviewed the publication at all stages of development to ensure that it accurately reflects the results of their literature searches and the consensus-based recommendations from the meeting experts. The authors determined final content, and all authors read and approved the final publication. The authors maintained complete control over the content of the study. No payments were made to the authors for the writing of this publication. Juliette Allport of Leading Edge (part of the Lucid Group), Burleighfield House, Buckinghamshire, UK subsequently supported incorporation of comments into final drafts for author approval, and editorial styling required by the journal. AbbVie paid Leading Edge for this work. CR received a fellowship grant/bursary from the Foundation of the University of Montreal Hospital Center (CHUM).
Introduction Psoriasis is a common chronic immune-mediated inflammatory disorder affecting 2–3% of the population.1 There are several significant comorbidities associated with this systemic illness including cardiovascular disease, inflammatory bowel disease and psoriatic arthritis.1,2 Clinical observation is also suggestive of comorbid depression among patients afflicted with skin diseases, with some studies estimating that around one-quarter of patients in dermatology practices have a psychiatric disorder.3,4 Several observational studies have assessed the rate of depression or depressive symptoms among patients with psoriasis. In a case–control study performed in a dermatology clinic,5 Akay and colleagues found a significantly higher prevalence of depressive symptoms (evaluated according to the Beck Depression Inventory [BDI]) in patients with psoriasis than healthy controls (58% vs. 20%, P < 0.01). In another case– control study,6 mean BDI-II score was significantly higher in participants with psoriasis compared with healthy controls (16.04 vs. 5.75, P < 0.001, BDI-II ≥13 is suggestive of depression). The prevalence of depression (assessed with the Center for Epidemiological Study Depression Scale) in patients with self-reported psoriasis was 48.7% in a cross-sectional study performed in the United States.7 Furthermore, a large population-based cohort study using data from the United Kingdom General Practice Research Database found that the risk of depression was significantly elevated in patients with psoriasis compared with controls (adjusted hazard ratio: 1.39; 95% CI:
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1.37, 1.41).8 A diagnosis of psoriatic arthritis may further increase the likelihood of depression, with a quasi-experimental study in 618 participants reporting that patients with psoriatic arthritis had a higher prevalence of depression (32.4%; 95% CI: 23.7, 41.1) than those with psoriasis alone (20.7%: 95% CI 15.1, 26.3).9 Similar to psoriasis, depression is a chronic disorder with significant morbidity and mortality. Depression has long thought to be caused by a combination of psychosocial and biological factors. In particular, monoamine dysfunction is considered key the pathophysiology of this disease. Recent evidence points towards interactions between the immune and central nervous systems playing a role in depression.10,11 It remains unclear if the elevated rate of depression among patients with psoriasis may be a primary disorder relating to cytokine dysregulation or a secondary disorder involving psychosocial factors. Therefore, it is important to understand the effect, if any, of current treatments on this comorbidity. Many psoriasis treatments, including topical corticosteroids, methotrexate and cyclosporine, target the immune system. An important driver of the immunopathogenesis of psoriasis includes upregulation of pro-inflammatory cytokines such as tumour necrosis factor (TNF), interleukin (IL)-12 and IL-23. These are attractive treatment targets and, accordingly, biologics such as TNF inhibitors (TNFi; adalimumab, etanercept, infliximab, golimumab and certolizumab) and IL-12/23 inhibitors (IL-12/23i; ustekinumab) have become important tools in
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Effects of biologics on depressive symptoms in psoriasis
the management of moderate-to-severe psoriasis. There is evidence suggestive of a benefit of TNFi in reducing cardiovascular disease, a common psoriatic comorbidity, in immune-mediated diseases such as psoriasis and rheumatoid arthritis.12–14 We were interested in any possible effects biologics may have on depression in patients with psoriasis. The primary objective of this systematic review was to describe the effect of biologics (TNFi and IL12/23i) on depressive symptoms (measured by validated depression rating scales) in adult patients with psoriasis. This is part of a larger project: the Canadian Dermatology-Rheumatology CoMorbidities Initiative. This group includes a panel of dermatologists, rheumatologists and residents based in Canada that has developed evidencebased recommendations on the management of comorbidities in dermatological and rheumatological diseases.15
3
Study screening
The titles and abstracts of articles were initially screened for inclusion by P.F. using our predetermined criteria (phase I). The full texts of selected articles were then independently assessed for inclusion in an unblinded fashion by P.F. and W.P.G. (phase II). Disagreement between the reviewers was resolved by consensus. Data extraction
Recommendations of the Preferred Items for the Reporting of Systematic Reviews Meta-Analysis (PRISMA) statement were followed as applicable.16
One reviewer (P.F.) extracted data and synthesized it in tabular format. Extracted data were triple checked for accuracy. We extracted data on study characteristics (design, participant age and sex, inclusion/exclusion criteria, sample size and study duration); comparator group (placebo or usual care); outcome measures (proportion of patients with depressive symptoms as defined by study investigators, depression assessment tool and mean score on depression rating scales); intervention type; method of analysis (intention-to-treat or per-protocol analysis); and study completion rate. The level of evidence for each included article was evaluated using the Oxford Center for Evidence-Based Medicine scale.18
Eligibility
Outcomes
We included randomized controlled trials (RCTs) that were performed in patients aged 18 years or older with a clinical or histological diagnosis of psoriasis and that used a standardized measure of depression (such as a depression rating scale). We included TNF-a inhibitors and IL-12/23 inhibitors currently approved for use in plaque psoriasis. We broadly defined depression to include the presence of ‘depressive symptoms’ as assessed by most rating scales. Because depressive symptoms can take weeks or months to resolve, we required studies to have a follow-up period of at least 12 weeks. In addition, studies must have used an intention-to-treat analysis. Study quality was assessed using the U.S. Preventive Services Task Force quality rating criteria for RCTs.17 Only studies considered ‘good’ or ‘fair’ according to these criteria were included. We excluded studies that failed to account for confounding effects of major systemic illness (e.g. recent myocardial infarction or malignancy) either by exclusion, adjustment or multivariate modelling.
Our primary outcome was a significant reduction in depression scores on depression rating scales. Our secondary outcome was a reduced proportion of depressed patients as measured by depression rating scales.
Methods
Search strategy
We searched PUBMED, EMBASE and the Cochrane Database for relevant studies performed in humans and published in English. No date limits were set. Search terms (MeSH headings) included psoriasis and depression or depressive symptoms. We hand-searched the reference lists of included articles for any additional relevant studies. We also searched the proceedings of the American Academy of Dermatology and European Academy of Dermatology and Venereology annual meetings from 2010 to 2012 to identify any potentially relevant abstracts.
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Risk of bias
We assessed the risk of bias in the selected RCTs by considering randomization sequence generation, allocation concealment, participant blinding, healthcare provider blinding, outcome assessor blinding and study attrition.16
Results We initially identified 305 articles in our literature search, of which four were eligible for inclusion in our analysis. Reasons for exclusion are shown in Fig. 1. All studies were of good quality and the level of evidence was 1b. All included adequate reporting of our key measures of bias and all used intention-totreat analysis. Of the included studies, three were RCTs19–21 that examined the effects of ustekinumab, adalimumab or etanercept, respectively, on depressive symptoms in patients with psoriasis. One additional study was an open-label extension of the etanercept-focused RCT.22 These studies had a combined sample size of 1946 patients. Study characteristics are presented in Table 1. No published RCTs were identified that evaluated the effects of infliximab, golimumab or certolizumab on depression or depressive symptoms in patients with psoriasis. Synthesis of results
All three RCTs demonstrated significant reductions in depression scores in patients treated with TNFi and IL12/23i with
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Figure 1 PRISMA flow diagram of study selection process.
12–24 weeks of follow-up19–21 (Table 2). Groups treated with ustekinumab and adalimumab demonstrated significant reductions in depression symptom scores at follow-up compared with baseline with no significant reduction in the placebo groups.19,20 In the trial comparing ustekinumab with placebo, there was a significantly lower proportion of people meeting the Hospital and Anxiety Depression Scale criteria for depression in the intervention group after 12 weeks (P < 0.001).19 In the study comparing etanercept with placebo, etanercept was associated with significantly greater improvements in both the BDI and Hamilton depression scores at 12 weeks.21 Although there was a nonsignificant between-group difference in the proportion of patients with depression at 12 weeks, the trend was towards a lower prevalence of depression in the etanercept group. In addition, in the open-label extension of this trial, such changes were sustained for up to 96 weeks in the case of etanercept.22
Discussion Depression is a common comorbidity in patients with psoriasis. A recent meta-analysis examining the rate of depression in psoriasis found a prevalence of 28% based on depression rating scales.23 When analysing studies with controls, the investigators found that patients with psoriasis were more likely to have depression than those without psoriasis (odds ratio [OR]: 1.57; 95% CI: 1.40, 1.76).
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Our systematic review continues the evaluation of this comorbidity in patients with psoriasis by examining the effect of psoriasis treatment on depressive symptoms. To our knowledge, this is the only systematic review on the use of biologics in patients with psoriasis and depression. Analysis of data from 1,946 participants indicates that TNFi and IL12/23i can significantly reduce depressive symptoms after 12–24 weeks of use in patients with moderate-to-severe psoriasis. There are several reasons why biologics may affect depressive symptoms in patients with psoriasis and depend on whether this comorbidity is a primary disorder relating to cytokine dysregulation or secondary disorder involving psychosocial factors. The immune system may play a role in the pathogenesis of depression. There is evidence that cytokines can not only access the central nervous system through blood–brain barrier transport proteins, but can also affect neuronal calcium regulation much like the monoamines implicated in depression.10,11,24,25 A recent meta-analysis examined levels of cytokines in patients meeting Diagnostic and Statistical Manual (DSM) criteria for major depression.25 The researchers found that levels of TNF-alpha were significantly elevated in patients with depression compared with controls without depression (weighted mean difference: 3.97; 95% CI: 2.24, 5.71). A placebo-controlled RCT evaluating infliximab in non-psoriatic patients with major depressive disorder found a significant reduction in depressive symptoms with
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Multicentre RCT in USA, Canada & Europe
Multicentre RCT in USA & Canada
Menter et al., 2010
Tyring et al., 2006
96
620
Inclusion: plaque psoriasis for >1 year, age > 18 years, BSA >5%, TNFi-na€ıve Exclusion: history of cancer, tuberculosis, neurological disease Inclusion: plaque psoriasis, age >18 years psoriasis, BSA >10%, prior systemic/phototherapy Exclusion: psychiatric disease, guttate/erythrodermic/pustular psoriasis, prior TNFi use, recent topical corticosteroids 464
1230
Inclusion: moderate-severe psoriasis, age >18 years, PASI >12, BSA >10%, candidate for systemic/phototherapy Exclusion: non-plaque psoriasis, serious systemic disease, malignancy, recent biologic use (3 months), recent systemic therapy (4 weeks), recent topical therapy (2 weeks), active tuberculosis
Inclusion: All patients who completed randomized controlled phase of trial (placebo and intervention)
Sample size (n)
Eligibility criteria
BSA, body surface area; PASI, Psoriasis Area Severity Index; SC, subcutaneous. *Based on trial data from Tyring et al.,21 included for discussion.
Open-label multicentre extension of study by Tyring et al.
Multicentre, cross-over RCT in USA, Canada & Europe
Langley et al., 2010
Krishnan et al., 2006*
Design
Study
Table 1 Characteristics of included clinical trials
Etanercept 50 mg SC twice weekly
Placebo
Not reported
45.6 (12.1)
45.8 (12.8)
43.3 Etanercept 50 mg SC twice weekly
Placebo
Not reported
70
65
65
70
69.0
47.0 (12.5)
Placebo
45.6
66.7
47.0 (12.1)
Ustekinumab 90 mg SC at weeks 0, 4, then q12 weeks Adalimumab 80 mg SC initial dose then 40 mg q2 weeks.
69.2
Male gender (%)
45.1 (12.1)
Mean age (years, SD)
Patient characteristics
Ustekinumab 45 mg SC at weeks 0, 4, then q12 weeks
Intervention
96
12
12
24
Follow-up duration (weeks)
Effects of biologics on depressive symptoms in psoriasis 5
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Good
Good
Good
Langley et al., 2010
Menter et al., 2010
Tyring et al., 2006 BDI-I (score >9 indicates depression) Ham-D (score >6 indicates depression)
ZDS (score >50 indicates depression)
HADS (score >9 indicates depression)
Depression rating tool
Mean change in depression score 1.7 (SD 3.1) vs. baseline (P < 0.001) 2.1 (SD 3.4) vs. baseline (P < 0.001) +0.21 (SD 2.8) vs. baseline (NS) 6.7 (95% CI: 10.1, 3.1) vs. baseline 1.5 (95% CI: 4.0, +1.0) vs. baseline BDI: 1.8 (95% CI: 0.6, 2.9) for etanercept vs. placebo Ham-D: 1.2 (95% CI: 0.4, 1.9) for etanercept vs. placebo
Prevalence of depression/ depressive symptoms (%) Baseline: 24.7 24 weeks: 12.8 (P < 0.001) Baseline: 31.1 24 weeks: 12.5 (P < 0.001) Baseline: 24.2 24 weeks: 26.7 (NS) Baseline: 32% 12 weeks: not reported Baseline: 37% 12 weeks: not reported Baseline: 34% 12 weeks: 16% (BDI) Baseline: 35% 12 weeks: 20% (BDI) (P = 0.16 for etanercept vs. placebo at week 12)
Intervention Ustekinumab 45 mg Ustekinumab 90 mg Placebo
Adalimumab
Placebo
Etanercept
Placebo
3.7
11.4
3.4
Lost to follow-up (%)
BDI, Beck Depression Inventory; HADS, Hospital and Anxiety Depression Rating Scale; Ham-D, Hamilton Rating Scale for Depression; ZDS, Zung Self-Rating Depression Scale. *U.S. Preventive Services Task Force quality rating criteria. †Oxford Center for Evidence-Based Medicine scale.
Study quality*
Study
Table 2 Outcome data on depression or depressive symptoms for included clinical trials
1b
1b
1b
Level of evidence†
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Effects of biologics on depressive symptoms in psoriasis
infliximab in those patients with higher baseline serum C-reactive protein and TNF levels, although there was no betweentreatment difference in change in depressive symptoms across the overall study population.26 Therefore, if depression in psoriasis is related to cytokine dysfunction (at least in part), then modifying circulating cytokine levels may affect depressive symptoms. An alternative explanation for the ability of biologics to reduce depressive scores relates to psychosocial factors such as improved quality of life and reduced social stigma with improved signs and symptoms of psoriasis. It is well established that psychosocial factors have a major impact on the course of both endogenous and reactive clinical depression. Likewise, there is strong evidence suggestive of the important role that psychological and social factors play in psoriasis. It has long been known that emotional stress can precipitate a flare of psoriasis27 and that patients with psoriasis can experience substantially reduced quality of life that may both impair social and occupational function. The quality of life among patients with psoriasis is comparable with many serious illnesses such as coronary disease and malignancy.28 Likewise, cutaneous illnesses can carry a high risk of stigma due to the visibility of skin lesions.29 The most likely explanation for the relationship between psoriasis and depression is multifactorial with a combination of genetic predisposition, cytokine dysfunction and psychosocial risk factors. Indeed, in the studies evaluated in this systematic review, quality of life, fatigue and Psoriasis Area Severity Index scores improved in parallel with depressive symptoms. Depression in patients with psoriasis may have substantial impact on more than just quality of life. Rheumatoid arthritis (RA) is another autoimmune disease with a high rate of depression.30 There is growing evidence of higher rates of mortality in depressed compared with non-depressed RA patients. Retrospective analysis of a cohort of 1290 RA patients found that the mortality risk increased with each additional unit on depression scale scores (OR: 1.35; 95% CI: 1.1,1.6).31 Likewise, another retrospective cohort analysis involving 22 131 patients with RA found a mortality risk among those with self-reported depression (hazard ratio: 1.3; P = 0.002).32 At present, there are no long-term mortality data on psoriasis patients with depression. However, given that patients with depression generally have higher all-cause mortality rates than the general population, it would not be unreasonable to assume this is the case in those with psoriasis as well. Given the high rates of concurrent illness, we propose several recommendations for management of depression in patients with psoriasis. We consider that it is reasonable to screen patients with psoriasis for depression when appropriate. The U.S. Preventive Services Task Force review on depression screening reported that asking two basic questions may be as effective at identifying patients with depression as more complex screening instruments.33 These include: ‘Over the past 2 weeks, have
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you felt down, depressed, or hopeless?’ and ‘Over the past 2 weeks, have you felt little interest or pleasure in doing things?’ A positive screen should initiative referral to an appropriate healthcare provider such as a family physician or psychiatrist. The three RCTs evaluated in this systematic review suggest a beneficial effect of TNFi and IL12/23i on depressive symptoms in patients with moderate-to-severe psoriasis. Further clinical trials that include prevalence of depression or change in depressive symptoms as primary endpoints and involve standardized psychiatric interviews are required to better understand the effect of biologics on depression in patients with psoriasis before recommendations on their use can be formulated. This systematic review has several limitations. Firstly, none of the included studies used DSM criteria to diagnose major depression. The scales and data from individual RCTs could not be combined. Depression rating scales are useful in measuring the severity of symptoms in depressed patients but they cannot replace a psychiatric interview as a diagnostic tool. Furthermore, the depression rating scales utilized in the included studies have several flaws that may affect their validity in detecting true depression. Many items on these scales include somatic symptoms resulting in ‘criterion contamination’.34 For example, the BDI has questions such as, ‘I can sleep as well as usual’ or ‘I am no more worried about my health than usual’. It is conceivable that patients with psoriasis without depression may have poorer sleep due to pruritus or they may worry about their health more than patients without psoriasis, thereby interfering with their true scores. It is not clear what relation, if any, these items have with true major depressive disorder. In addition, concomitant use of antidepressants during the interventions was not consistently reported in the studies so any potential confounding effect cannot be accounted for in this review. Therefore, the publications used in this analysis cannot be used to assess the effect of biologics on depression, but can only be used in an assessment of the effect of biologics on depressive symptoms in patients with scores suggestive of clinical depression. An additional limitation of this review is the lack of published evidence on the effect of other immune-modifying treatments such as methotrexate or cyclosporine on depressive symptoms. Given that these agents can also lower TNF levels, such treatments may be beneficial in patients with psoriasis and depression. In conclusion, three high-quality RCTs have demonstrated a reduction in depression scores on common depression rating scales after 12–24 weeks of TNFi or IL12/23i treatment in patients with psoriasis. While such scales used in conjunction with signs and symptoms are suggestive of major depressive disorder, a robust RCT including standardized DSM psychiatric interviews is required to better determine the clinical significance of these findings. In the interim, it is reasonable to screen patients with psoriasis for depression when appropriate and refer accordingly.
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Acknowledgements We would like to acknowledge Dr. Terrence Callanan, Professor of Psychiatry at Memorial University of Newfoundland, St. John’s, Newfoundland, Canada for providing advice on this manuscript.
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