Economic Burden of Psoriasis in the United States A Systematic Review

Transcription

1 Clinical Review & Education Review A Systematic Review Elizabeth A. Brezinski, MD; Jaskaran S. Dhillon; April W. Armstrong, MD, MPH IMPORTANCE The total cost of psoriasis in the United States is unknown. Defining the US economic burden of psoriasis is needed because it provides the foundation for research, advocacy, and educational efforts. Supplemental content at jamadermatology.com OBJECTIVE To determine the US economic burden of psoriasis from a societal perspective. EVIDENCE REVIEW PubMed and MEDLINE databases were searched between January 1, 2008, and September 20, 2013, for economic investigations on the direct, indirect, intangible, and comorbidity costs of adult psoriasis in the United States. The base year costs were adjusted to 2013 US dollars using the Consumer Price Index for All Urban Consumers and multiplied by the estimated number of US patients with psoriasis in 2013 to determine the 2013 psoriasis cost burden. FINDINGS Among 100 identified articles, 22 studies were included in the systematic review. The direct psoriasis costs ranged from $51.7 billion to $63.2 billion, the indirect costs ranged from $23.9 billion to $35.4 billion, and medical comorbidities were estimated to contribute $36.4 billion annually in 2013 US dollars. Patients with psoriasis would pay a lifetime cost of $ for relief of physical symptoms and emotional health; however, intangible cost data are limited. The annual US cost of psoriasis amounted to approximately $112 billion in CONCLUSIONS AND RELEVANCE The economic burden of psoriasis is substantial and significant in the United States. JAMA Dermatol. 2015;151(6): doi: /jamadermatol Published online January 7, Author Affiliations: Department of Dermatology, University of California Davis, Sacramento (Brezinski, Dhillon); Department of Dermatology, University of Colorado Denver (Armstrong). Corresponding Author: April W. Armstrong, MD, MPH, Department of Dermatology, University of Colorado Denver, E 17th Ave, Mail Stop 8127, Aurora, CO (aprilarmstrong@post.harvard.edu). Psoriasis is a chronic, inflammatory skin condition that affects 3.2% of the US population, and many patients with psoriasis require long-term care. 1 Patients with psoriatic diseases not only have skin and joint impairment but also experience serious medical comorbidities, such as increased cardiovascular events and depression. 2-8 Furthermore, patients with psoriasis often report difficulties in social interactions and pronounced psychological distress associated with having the disease. 9,10 Long-term management of psoriasis may incur substantial cumulativeexpenses. Costsassociatedwithpsoriasisarenumerousand may be viewed from several different perspectives, including the patient, insurance companies, and society. Typical sources of cost have been classified as direct expenses from the primary disease, indirect costs determined by loss of work productivity, and intangible costs, such as the potential for restricted activities and poor selfimage, which are more difficult to measure. However, literature examining the overall costs of the disease burden and therapies used to treat psoriasis in the United States is lacking. Furthermore, much of the available literature on the US economic burden of psoriasis focuses on a single measure of cost, such as the direct cost. 11,12 Therefore, a pressing need exists to conduct a comprehensive study from a societal perspective that captures the direct, indirect, intangible, and comorbidity costs associated with psoriasis. The primary objective of this article is to provide an up-todate, comprehensive analysis of the literature on the economic burden of psoriasis in the United States. The direct, indirect, intangible, and comorbidity costs of psoriasis are summarized based on a systematic review of the most recent US literature and adjusted to 2013 US dollars (US $). Methods Search Strategy We conducted a search of the literature using the PubMed and MEDLINE databases for articles that examined costs associated with psoriasis. Our search was limited to English-language articles published between January 1, 2008, and September 20, The search was performed using the Medical Subject Headings psoriasis AND costs and cost-analysis, cost of illness, orhealth care costs. We also manually searched the reference lists of relevant articles for additional articles to review. jamadermatology.com (Reprinted) JAMA Dermatology June 2015 Volume 151, Number 6 651

2 Clinical Review & Education Review Figure. Flowchart for the Economic Burden of Psoriasis in the United States Systematic Review of the Literature 164 Records identified through database searching 100 Records after duplicates removed 100 Records screened 31 Full-text articles assessed for eligibility 22 Studies included in the systematic review 1 Additional record identified through other sources 69 Records excluded after reviewing abstracts 44 Another country 13 Not a trial or review 5 No outcome of interest 3 Another type of psoriasis 2 Pediatric psoriasis study 2 Other 9 Full-text articles excluded 3 Another country 3 Review with data outside inclusion dates 2 No outcome of interest 1 Review with US primary data already included This flowchart shows the number of studies identified, screened, reviewed, and included or excluded during study selection. Inclusion Criteria We limited the results to controlled trials, meta-analyses or systematic reviews of controlled trials, and survey studies that were published within the past 5 years to account for the recent inclusion of biologic therapy data in relevant articles. Titles and abstracts were screened for information on costs related to adult psoriasis care, including outpatient and hospital-based disease management, pharmacotherapy, decreased work productivity, comorbid medical conditions, and intangible costs. Data Abstraction Two of us (E.A.B. and J.S.D.) independently extracted the data, and any disagreements were resolved by consensus among the 3 of us. Studies were assessed using Strength of Recommendation Taxonomytogradethestrengthofkeytreatmentrecommendationsand quality of evidence. 13 Definition of Costs The direct, indirect, intangible, and comorbidity costs were assessed. The direct costs include medical costs related to (1) specialist medical evaluations, (2) hospitalization, (3) prescription medications, (4) phototherapy, (5) medication administration costs, (6) laboratory tests and monitoring studies, and (7) over-the-counter medications and self-care products. Costs for these services and products were obtained from several sources, including the averagewholesaleprice(awp), wholesaleacquisitioncost, MedicarePhysician Fee Schedule and Clinical Laboratory Fee Schedule, and patient-reported US $ values. The indirect costs are determined by absenteeism or presenteeism. Absenteeism is the value of lost work productivity due to missing work for health care appointments, sick leave, or unemployment. Presenteeism is the value of impaired work productivity when on the job owing to disease activity. Intangible costs are a measure of the negative effect of psoriasis on quality of life. Willingness-to-pay scenarios are one method to determine these costs. Comorbidity costs measure the medical evaluations, treatment, and laboratory monitoring that can be directly attributed to comorbid conditions associated with psoriasis. Comorbidity costs are considered an additional source of cost because the value is a result of medical conditions that are associated with, but managed separately from, psoriasis. Costs in 2013 US $ were estimated by adjusting for the rate of inflation using the Consumer Price Index for All Urban Consumers (CPI-U), which covers 88% of the US population. 14,15 The CPI-U is constructed by the US Bureau of Labor Statistics. It is a measure of the mean change over time in the prices paid by urban customers for a market basket of consumer goods and services purchased for day-to-day living. Costs were adjusted to 2013 US $ using the CPI-U from the base year of costs defined in each publication, or the year of publication if the base year was not defined in the article, compared with the October 2013 CPI-U. 14 The annual direct, indirect, and comorbidity costs were calculated by multiplying the cost per patient adjusted to 2013 US $ by the estimated number of US individuals in 2013 with psoriasis. 1 For the intangible cost burden, a lifetime cost for the 2013 psoriasis population was calculated by multiplying the cost per patient in 2013 US $ by the estimated number of US individuals with psoriasis in Results Study Selection An initial review of the literature generated 100 articles that matched the search criteria after removing duplicate studies, with 1 article obtained through a manual search of the literature. 15 After reading the abstracts, 31 studies underwent full-text review. We excluded 9 articles for the following reasons: reporting data from another country (n = 3), reviewing primary data outside the dates of inclusion (n = 3), reporting no outcome of interest (n = 2), or reviewing primary data already included in publications selected for this review (n = 1). The remaining 22 studies were included in the systematic review (Figure). Study characteristics for each article are listed in Table 1, outcome data are given in the etable in the Supplement, and outcomes of interest are summarized in Table 2. Direct Costs An early estimate of direct health care expenses attributed to psoriasis in the United States was $694.6 million, when the estimated prevalence of psoriasis was 1.4 million individuals (1997 US $). 11 From the literature review, 19 studies examined the direct costs associated with psoriasis between 2008 and Overall Direct Cost In a retrospective review, Fowler et al 19 found that the direct cost per patient per month for a psoriasis cohort was $614 (95% CI, $ JAMA Dermatology June 2015 Volume 151, Number 6 (Reprinted) jamadermatology.com

3 Review Clinical Review & Education Table 1. Cost of Psoriasis Treatment: Study Characteristics Source (Base Year US $) Type of Study Study Population Characteristics Time Horizon Direct and Indirect Health Care Cost Studies Bhutani et al, (NR) Cross-sectional survey of patients with psoriasis 5604 Patients with psoriasis (mild, moderate, and 3mo severe) Gunnarsson et al, (2008) Retrospective study 873 Patients with psoriasis of all severities, y controls Parsi et al, (2009) CEA and comparative study Patients with psoriasis of all severities (32 with online 24 wk visits, 32 with in-office visits) Yu et al, (2007) Retrospective case-control study, matched Patients with psoriasis (mild, moderate to 1y severe), controls Fowler et al, (2006) Retrospective case-control study, matched Patients with psoriasis of all severities, y controls Systemic Therapy Cost Studies Lin et al, (NR) Retrospective cross-sectional study Patients with psoriasis of all severities 1 y Staidle et al, (2010) Pharmacoeconomic analysis Patients with moderate to severe psoriasis (number NR) 1 y Alora-Palli et al, (2008) Pharmacoeconomic analysis 60 Patients with moderate psoriasis 2 y Beyer and Wolverton, (2008) Pharmacoeconomic analysis Patients with psoriasis (number and severity NR) 1 y Yentzer et al, (2007) Comparative study 1000 Patients with severe psoriasis 1 y Biologic Agent Cost Studies Ahn et al, (2010) CEA literature review 7784 Patients with moderate to severe psoriasis 12 wk Villacorta et al, (2011) CEA Patients with psoriasis (number and severity NR) 3 y Leonardi et al, (2011) Open-label extension study 1256 Patients with moderate to severe psoriasis 1 y Liu et al, (2011) Mixed treatment comparison meta-analysis Patients with moderate to severe psoriasis (number NR) 12 wk Bonafede et al, (2011) Retrospective observational study and Patients with psoriasis (severity NR) 4 y pharmacoeconomic analysis Anis et al, (NR) Meta-analysis and CEA Patients with moderate to severe psoriasis (number NR) wk Martin et al, (2010) Randomized, active comparator trial and CEA 903 Patients with moderate to severe psoriasis 1 y Wu et al, (2006) Retrospective study and CEA of etanercept 578 Patients with moderate to severe psoriasis 1 y Nelson et al, (2006) Review of the literature ( ) and CEA Patients with psoriasis (number and severity NR) 12 wk Intangible Health Care Cost Study Delfino et al, (NR) Questionnaire 40 Patients with psoriasis of all severities NA Medical Comorbidity Direct Health Care Cost Studies Han et al, (NR) Matched case-control study 7971 Patients with moderate to severe psoriasis, 1y controls Kimball et al, (2007) Matched case-control study Patients with psoriasis (mild, moderate to severe) having comorbidity, controls with psoriasis (mild, moderate to severe) 6mo Abbreviations: CEA, cost-effectiveness analysis; NA, not applicable; NR, not reported; US $, US dollars. $634) compared with $284 (95% CI, $273-$296) for the general population (2006 US $). Similarly, Yu et al 18 observed that patients with psoriasis had statistically significantly greater mean (SD) direct annual health care costs than the general population ($5529 [$14 905] vs $3509 [$10 065]) (2007 US $). Gunnarsson et al 12 determined that the mean annual direct health care insurer expenses and patient out-of-pocket expenses were $5021 and $1418, respectively, for patients with psoriasis compared with $4102 and $967 for the general population (P <.001) (2008 US $). Bhutani et al 16 found that the mean annual out-of-pocket expense for patients with psoriasis was $2528 (US $ not reported). Direct Costs Owing to Topical Therapy Few studies have examined the cost of topical medications for psoriasis treatment. One study 22 found that 15% liquor carbonis distillate in a topical formulation was more cost-effective after 12 weeks oftreatmentthantopicalcalcipotriolcreamamongpatientswithpsoriasis of moderate disease severity achieving a Psoriasis Area and Severity Index (PASI) of 75 ($69 vs $2657) (2008 US $). Direct Costs Owing to Phototherapy Three articles 21,23,24 examined costs associated with induction or maintenance phototherapy with home-based and office-based narrowband UV-B and psoralen UV-A. Induction therapy with psoralen UV-A for 12 weeks cost $4235 (2008 US $). 23 The annual phototherapy maintenance costs ranged from $1414 to $6676 for officebased narrowband UV-B, from $2590 to $2768 for home-based narrowbanduv-b, andfrom$3347to$7697forpsoralen UV-A(2010 US $ to 2008 US $, respectively). 21,23,24 The annual cost of maintenance phototherapy averaged $5713 per patient (2010 US $). 21 Direct Costs Owing to Systemic Therapy The cost of systemic therapies includes expenses of the medication itself, medication administration, laboratory monitoring, and office visits to evaluate treatment efficacy. Systemic therapies for the treatment of moderate to severe psoriasis that are reviewed herein include methotrexate, cyclosporine, and acitretin and the biologic medications adalimumab, alefacept, etanercept, infliximab, and ustekinumab. Alefacept is no longer marketed or sold in the United jamadermatology.com (Reprinted) JAMA Dermatology June 2015 Volume 151, Number 6 653

4 Clinical Review & Education Review Table 2. Cost of Psoriasis Treatment: Outcomes of Interest Source (Base Year US $) Primary Outcomes of Interest Secondary Outcomes of Interest Direct and Indirect Health Care Cost Studies Bhutani et al, (NR) Out-of-pocket health care expenses for psoriasis for the past 3 mo by variable Total mean out-of-pocket costs in 3 mo and 1 y, out-of-pocket costs adjusted for disease severity Gunnarsson et al, (2008) Parsi et al, (2009) Mean annual direct health care insurer expenditure, mean annual out-of-pocket expenditure Online and in-office costs per patient, cost of patient time per visit with a rate of $0.49/min Aggregate annual national expenditures attributed to psoriasis in patients with insurance (sensitivity analysis) Cost-effectiveness analysis results Yu et al, (2007) Annual health care cost of psoriasis vs control Annual health care cost of moderate to severe vs mild psoriasis Fowler et al, (2006) Incremental direct cost in PPPM, incremental indirect cost in PPPM Total direct cost univariate analysis in PPPM, total indirect cost univariate analysis in PPPM Systemic Therapy Cost Studies Lin et al, (NR) Psoriasis-specific annual total drug costs NA Staidle et al, (2010) Annual cost of maintenance therapy Cost-effectiveness by a PASI of 75, cost-effectiveness by a DLQI-MID Alora-Palli et al, (2008) Cost of received treatment per patient Cost-effectiveness by a PASI of 75 at wk 12 and wk 18 Beyer and Wolverton, (2008) Annual cost of induction plus maintenance therapy AWP trends from 2000 to 2008 and percentage change in AWP (year 1), annual cost of maintenance therapy (year 2) Yentzer et al, (2007) Annual cost to patient, annual cost to insurance provider Annual cost to insurance provider if 80% of 1000 patients selected biologics, annual cost to insurance provider if 20% of 1000 patients received phototherapy and insurance covered 100% of costs Biologic Agent Cost Studies Ahn et al, (2010) 12-wk Cost of biologic therapy Cost per patient achieving a PASI of 75 during 12 wk, cost per patient achieving a DLQI-MID during 12 wk Villacorta et al, (2011) Leonardi et al, (2011) Liu et al, (2011) Annual direct cost per patient in induction year and maintenance year, annual indirect cost per patient in induction year and maintenance year Annual cost implications of adalimumab dosage escalation to 40 mg once weekly Cost per additional responder with a PASI of 75 during 12 wk Incremental cost-effectiveness ratio (US $ per QALY gained) at a willingness-to-pay threshold of $ to $ NA Cost per additional remitter with a PASI of 90 during 12 wk Bonafede et al, (2011) Cost per treated patient with psoriasis NA Anis et al, (NR) Optical sequence of biologic treatments Individual annual biologic treatment costs and additional cost Martin et al, (2010) Sensitivity analysis of the cost per responder NA with a PASI of 75 Wu et al, (2006) Mean annual total dose and cost of etanercept Mean annual total dose and cost of etanercept at 50 mg/wk at 100 mg/wk Nelson et al, (2006) 12-wk Cost of maintenance treatment Cost per patient achieving a PASI of 75 during 12 wk, cost per patient achieving a DLQI-MID during 12 wk Intangible Health Care Cost Study Delfino et al, (NR) Willingness to pay for health-related quality of life NA Medical Comorbidity Direct Health Care Cost Studies Han et al, (NR) Total mean annual health care costs NA Kimball et al, (2007) Total health care cost during 6 mo Cost difference during 6 mo unadjusted, cost difference during 6 mo adjusted for age, sex, and psoriasis severity Abbreviations: AWP, average wholesale price; DLQI-MID, Dermatology Life Quality Index Minimal Important Difference; NA, not applicable; NR, not reported; PASI, Psoriasis Area and Severity Index; PPPM, per patient per month; QALY, quality-adjusted life year; US $, US dollars. States. Costs are stratified by induction therapy and maintenance treatment when reported in the literature. Five studies 15,20,21,23,28 evaluated the direct cost associated with systemic therapy for moderate to severe psoriasis. In 2008, the cost of induction and maintenance therapy during the first year of treatment with biologics was highest for alefacept ($27 577), followed by etanercept (50 mg weekly) ($26 862), infliximab ($23 639), and adalimumab ($23 538) (2008 US $). 23 In another study, 15 ustekinumab (90 mg) cost more during the induction year than ustekinumab (45 mg) and etanercept (50 mg) weekly ($ vs $ vs $31 391) (2011 US $). The annual cost of maintenance therapy was estimated to average $ per patient for traditional systemic medications and $ for biologics (2010 US $). 21 Among traditional systemic therapies, annual maintenance treatment with methotrexate cost $1197 for 7.5 mg weekly and $1393 for 15 mg weekly (2008 US $), cyclosporine treatment cost $7768 for 300 mg daily (2008 US $) and $9999 to $ for 400 mg daily (2008 and 2010 US $, respectively), and acitretin therapy (25 mg daily) cost $9163 to $ (2008 and 2010 US $, respectively). 21,23 From the private payer s perspective, the mean (SD) annual psoriasisspecific total drug cost was $1309 ($2760) (US $ not reported). 20 One study 28 found that the annual cost of biologic treatment with etanercept, adalimumab, and infliximab per patient with psoriasis was greater during maintenance treatment than during induction therapy. 654 JAMA Dermatology June 2015 Volume 151, Number 6 (Reprinted) jamadermatology.com

5 Review Clinical Review & Education The percentage change in AWP from 2000 to 2008 differed depending on the type of systemic therapy and the brand name of the medication. 23 The greatest increase in AWP was 315.7% for brand-namemethoxsalen. 23 Biologicmedicationshadincreasingcost trends ranging from 14% for infliximab to 46.1% for etanercept during 9 years. 23 Alefacept had no change in AWP during 6 years. 23 Four studies 25,27,30,32 reported cost-effectiveness analyses with biologic agents using the PASI response, the Dermatology Life Quality Index Minimal Important Difference (DLQI-MID), or the incremental cost per quality-adjusted life-year. Among 12-week biologic induction regimens approved by the US Food and Drug Administration (FDA), adalimumab and infliximab had the lowest cost per patient achieving a PASI of 75 ($11 869) and a DLQI-MID ($5405), respectively, while alefacept had the highest cost per patient achieving a PASI of 75 ($ ) and a DLQI-MID ($28 768) (2010 US $). 25 Among FDA-approved biologic maintenance regimens, infliximab and adalimumab had the lowest cost per patient achieving a PASI of 75 ($10 422) and a DLQI-MID ($3511), respectively, while alefacept had the highest cost per patient achieving a PASI of 75 ($75 623) and a DLQI-MID ($27 136) (2006 US $). 32 Liu et al 27 reported the cost per patient achieving a PASI of 75 at 12 weeks for adalimumab, etanercept, infliximab, and ustekinumab. They found that adalimumab had the lowest cost ($9756; 95% CI, $8668- $11 131) andustekinumab(90mg) hadthehighestcost($25 327; 95% CI, $ $27 332) per responder with a PASI of 75 (2011 US $). In a sensitivity analysis, Martin et al 30 extrapolated the cost per responder with a PASI of 75 to 52 weeks and determined that induction and maintenance therapy cost $ for etanercept comparedwith$44 605forustekinumab(2010US$). At1year, Villacorta et al 15 found that ustekinumab (45 mg) surpassed etanercept (50 mg) for the outcome of incremental cost per quality-adjusted lifeyear at US willingness-to-pay thresholds ($ ) (2011 US $). Anis et al 29 investigated one optimal sequence of biologic treatments based on incremental cost-effectiveness. They determined that the first-choice agent was adalimumab, followed by etanercept (50 mg) weekly, etanercept (50 mg) twice weekly, infliximab, and then alefacept. Dosage escalation with biologic agents may be practiced when patients with psoriasis demonstrate an inadequate response to FDAapproved treatment regimens. Two studies 26,31 examined the cost implications of biologic dosage escalation. Adalimumab dosage escalation to 40 mg weekly increased the cost by $1006 per patient annually compared with FDA-approved adalimumab dosing ($23 464) (2011 US $). 26 Etanercept dosage escalation from 50 mg twice weekly by a mean of 827 mg annually cost $ (95% CI, $ $33 666) compared with $ for 3200 mg when taken as directed (2006 US $). 31 Direct Costs Stratified by Disease Severity The question of whether more severe disease leads to increased health care costs is relevant to determining the economic burden of psoriasis. In one study, 18 patients having psoriasis with moderate to severe skin disease, defined by the use of 1 or more nontopical systemic therapies, had significantly greater annual health care costs than patients with psoriasis having mild skin disease ($ vs $5011, P <.001). The cost difference remained significant after excludingthecostofsystemictherapy.similarly,bhutanietal 16 found that patients with psoriasis having severe skin disease had significantly increased direct out-of-pocket expenses than patients with mild disease ($563; 95% CI, $278-$847; P <.001). Direct Costs Associated With Novel Models of Health Care Delivery One study 17 compared the cost-effectiveness of follow-up psoriasis management in the conventional in-office setting with a patientcentered online model. The cost of online care was 1.7 times less than the cost of in-person visits ($315 vs $576) (2009 US $). 17 Indirect Costs The indirect costs emerge with absenteeism (the value of work productivity due to missing work) and presenteeism (the value of impaired work productivity when on the job owing to disease activity). Among patients with psoriasis having moderate to severe disease, 40% reported that psoriasis is a problem or a large problem in everyday life. 35 The annual indirect costs may exceed the direct costs. 36 In 2005, one investigation found that lost productivity contributes $121 million annually to the economic burden of psoriasis, including $57 million in lost workdays and $30 million in restricted activity days. 37 Furthermore, an estimated $9.5 million would be lost in future earnings because of premature death among patients with psoriasis. 37 In 2006, the indirect costs owing to absenteeism totaled $7.7 billion, and presenteeism contributed $8.9 billion to the economic burden of psoriasis, when the US prevalence of psoriasis was estimated to be 4 million. 36 Two studies 15,19 reported incremental costs associated with lost work productivity among patients with psoriasis. The mean incremental cost of lost work productivity among patients with psoriasis of any disease severity compared with the general population was $129 (95% CI, $93-$165) per patient per month or $1548 annually per patient (2006 US $). 19 The burden due to the indirect incremental costs was 40% of the total annual incremental cost of psoriasis in this study. Among patients with psoriasis having moderate to severe disease, patients taking ustekinumab (45 or 90 mg) had annual indirect costs of $471, while patients taking etanercept (50 mg) had indirect costs of $6034 and $4903 during the induction and maintenance years, respectively. 15 Intangible Costs The negative effect of psoriasis on quality of life contributes an intangible cost. Intangible costs are difficult to measure. A willingnessto-pay model is one surrogate measure for the influence of psoriasis on overall quality of life. The 2005 study by The Lewin Group 37 found that individual patients with psoriasis were willing to pay $1114 annually for symptom relief or $2.3 billion per year for all patients with psoriasis after adjusting for disease severity. In a willingnessto-pay questionnaire examining 8 intangible domains of healthrelated quality of life, Delfino et al 33 found that patients with psoriasis were willing to pay the greatest lifetime cost for physical comfort and emotional health ($2000 each), followed by the ability to work or volunteer ($1600). Comorbidity Costs From the literature review, 2 articles 6,34 reported health care costs associated with medical comorbidities. Among patients with psoriasis having moderate to severe disease, those with a psychiatric disorder contributed significantly more to the annual direct health care cost than patients with psoriasis not having a psychiatric dis- jamadermatology.com (Reprinted) JAMA Dermatology June 2015 Volume 151, Number 6 655

6 Clinical Review & Education Review Table 3. Estimated (2013 US $) Source of Costs Annual Cost per Patient With Psoriasis (Base Year US $), $ a Annual Cost per Patient With Psoriasis Adjusted to 2013 US $ Using the CPI-U, $ Annual Cost for Psoriasis Population Adjusted to 2013 US $ Using the CPI-U, Billion $ b Estimate of direct health care costs Low 6439 (2008) High 7368 (2006) Estimate of indirect health care costs Low 2784 (2006) High 4132 (2006) Medical comorbidity direct health care costs 4368 (2007) Intangible health care costs (2008) Lifetime cost c 85.1 Lifetime cost c Lifetime cost c Total annual costs NA (Low estimate) to (high estimate) 112 (Low estimate) to 135 (high estimate) d Abbreviations: CPI-U, Consumer Price Index for All Urban Consumers; NA, not applicable. a The base year was determined by the year of publication. b The US psoriasis population was estimated in 2013 to be 7.4 million. 1 c One-time cost. d Does not include intangible health care costs. order ($ vs $10 363, P <.001) (US $ not reported). 6 Another article 34 examined patients with psoriasis having the following comorbidities: psoriatic arthritis, cardiovascular disease, depression, diabetes mellitus, hyperlipidemia, hypertension, obesity, cerebrovascular disease, or peripheral vascular disease. Compared with a psoriasis cohort without any known comorbidities, patients with at least 1 of the 9 comorbidities had a significantly greater adjusted difference in total health care costs during 6 months ($2184, P <.001). The 6-month mean (SD) health care cost for patients with psoriasis having comorbidities was $4994 ($12 319) (2007 US $). Specifically, patients with psoriasis having comorbid psoriatic arthritis may contribute $3320 more per patient annually to the economic burden of psoriasis than patients having only a diagnosis of psoriasis. Discussion This is among the first systematic reviews to synthesize the available data for the US economic burden of psoriasis attributed to 4 major sources of cost (direct, indirect, intangible, and comorbidity) from a societal perspective. We provide the reader with a comprehensive total cost of psoriasis using 2013 US $ (Table 3). Our review shows that patients with psoriasis have significantly greater health care costs in all 4 cost sources analyzed and that the burden is driven largely by the direct costs. When adjusted to 2013 US $, the annual direct cost of psoriasis ranges from $51.7 billion (low estimate) 12 to $63.2 billion (high estimate) 19 for the US psoriasis population (strength of recommendation, A; level of evidence, 2). The indirect costs contribute between $23.9 billion (low estimate) 19 and $35.4 billion (high estimate) 36 to the annual economic burden of psoriasis (strength of recommendation, B; level of evidence, 2). Medical comorbidity costs were estimated to contribute $36.4 billion annually (strength of recommendation, B; level of evidence, 2). 34 Intangible costs amountedtoaonce-per-lifetimecostof$11 498perpatientwithpsoriasis, or a one-time $85.1 billion cost for the 2013 US psoriasis population(strengthofrecommendation,b;levelofevidence,2). 33 Insum, the annual US economic burden of psoriasis ranged from $112 billion to $135 billion in 2013 US $. The direct health care costs are significantly greater for patients with psoriasis than for the general population and are also higher for patients with increasing psoriasis disease severity. The incremental annual direct health care cost per patient with psoriasis ranged from $900 to $2020 compared with a member of the general population. 18,19 More direct costs with greater disease severity may be attributed to increased frequency of seeking medical attention, higher rates of treatment failure, and greater comorbidities. 38 A patient-centered online care model appeared to be cost saving and effective compared with standard in-office care. 17 A significant portion of the current literature only assessed costs of systemic therapies for moderate to severe psoriasis without determining cost-effectiveness. For example, methotrexate had the lowest direct cost, followed by cyclosporine and acitretin. 21,23 The mean direct cost of phototherapy was less than that of most systemic therapies, and phototherapy may be more cost-effective than biologic medications according to some studies. 21,23,24 Long-term cost-effectivenessmodelsforsystemicandbiologicdrugsareneeded to provide valuable algorithms for treatment selection. Depending on their similarity and price point, biosimilar agents may represent a form of more cost-effective biologic therapies. The indirect costs due to absenteeism and presenteeism may account for up to 40% of the economic burden of psoriasis. 19 Estimates of the indirect costs owing to psoriasis before our study s inclusion period were greater than $16 billion annually, with an approximately equal contribution from absenteeism and presenteeism. 36 Developing medications with excellent efficacy and safety profiles may significantly reduce the indirect costs associated with psoriasis. Intangible costs estimate the economic burden of psychosocial distress experienced by patients owing to psoriasis. One method for determining intangible costs is willingness-to-pay questionnaires. Our review found that patients were willing to pay the most for physical comfort and emotional health. 33 In sum, an individual patient would pay a one-time cost of up to $ in 2013 US $ to eliminate negative effects of psoriasis in 8 domains of physical and emotional health. 33 Patients with psoriasis having medical comorbidities had significantly greater health care expenditures relative to those without comorbidities and the general population. Among patients with psoriasishavingcomorbidities, medicalandpsychiatricdisordersmay add between $4368 (2007 US $) 34 and $7275 (US $ not reported) 6 per patient to the annual psoriasis cost burden. Because the strength 656 JAMA Dermatology June 2015 Volume 151, Number 6 (Reprinted) jamadermatology.com

7 Review Clinical Review & Education of association varies between psoriasis and the different comorbidities, it is a challenge to determine the cost of comorbidities solely attributable to psoriasis at this time. The findings of this systematic review need to be interpreted in the context of the available primary literature. The source of the direct costs was not uniform across cost analyses. For example, the price of systemic medications can be reported using the AWP or the wholesale acquisition cost. Primary data on the cost of dosage escalation with biologic therapies are scarce; literature on the economic burden of combination therapy and switching systemic medicationsrelativetoinitialmonotherapyregimensisunavailabletodate in the United States. A Spanish study 39 reported that switching biologic therapies was less costly than temporary biologic dosage escalation for patients with psoriasis who experienced a suboptimal response to maintenance treatment. Most cost-effectiveness investigations for biologics were examined after 12 weeks of treatment. 27,30,32 Longer-term cost-effectiveness analyses are needed in comparative effectiveness research. Many articles examined only patients with moderate to severe psoriasis rather than patients with all disease severities. The data from these studies may underestimate the total psoriasis cost burden. Conclusions In conclusion, patients with psoriasis incur annual health care costs that are significantly greater than those of the general population and may amount to $135 billion annually (2013 US $). In the United States, the economic burden of psoriasis is substantial because this disease results in considerable negative physical, psychiatric, and social consequences. A research gap exists in examining the costeffectiveness of therapies, in which we need to account for all relevant aspects of the disease burden. Defining the economic burden of psoriasis from a societal perspective is the foundation for innovating and providing access to cost-effective therapies that will result in improved patient outcomes. ARTICLE INFORMATION Accepted for Publication: September 3, Published Online: January 7, doi: /jamadermatol Author Contributions: Drs Brezinski and Armstrong had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Brezinski, Armstrong. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: All authors. Critical revision of the manuscript for important intellectual content: Brezinski, Armstrong. Statistical analysis: Brezinski, Armstrong. Study supervision: Armstrong. Conflict of Interest Disclosures: Dr Armstrong reported serving as an investigator for or consultant to AbbVie, Amgen, Celgene, Janssen, Lilly, Merck, Pfizer, and UCB. No other disclosures were reported. REFERENCES 1. Rachakonda TD, Schupp CW, Armstrong AW. Psoriasis prevalence among adults in the United States.JAm Acad Dermatol. 2014;70(3): Armstrong AW, Harskamp CT, Armstrong EJ. The association between psoriasis and hypertension: a systematic review and meta-analysis of observational studies. J Hypertens. 2013;31(3): Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB, Gelfand JM. Prevalence of cardiovascular risk factors in patients with psoriasis. J Am Acad Dermatol. 2006;55(5): Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006;296(14): Armstrong EJ, Harskamp CT, Armstrong AW. Psoriasis and major adverse cardiovascular events: a systematic review and meta-analysis of observational studies. J Am Heart Assoc. 2013;2(2): e doi: /jaha Han C, Lofland JH, Zhao N, Schenkel B. Increased prevalence of psychiatric disorders and health care associated costs among patients with moderate-to-severe psoriasis. J Drugs Dermatol. 2011;10(8): Armstrong AW, Harskamp CT, Ledo L, Rogers JH, Armstrong EJ. Coronary artery disease in patients with psoriasis referred for coronary angiography. Am J Cardiol. 2012;109(7): Armstrong AW, Lin SW, Chambers CJ, Sockolov ME, Chin DL. Psoriasis and hypertension severity: results from a case-control study. PLoS One. 2011;6 (3):e doi: /journal.pone Kimball AB, Jacobson C, Weiss S, Vreeland MG, Wu Y. The psychosocial burden of psoriasis. Am J Clin Dermatol. 2005;6(6): Weiss SC, Kimball AB, Liewehr DJ, Blauvelt A, Turner ML, Emanuel EJ. Quantifying the harmful effect of psoriasis on health-related quality of life. J Am Acad Dermatol. 2002;47(4): Javitz HS, Ward MM, Farber E, Nail L, Vallow SG. The direct cost of care for psoriasis and psoriatic arthritis in the United States. J Am Acad Dermatol. 2002;46(6): Gunnarsson C, Chen J, Rizzo JA, Ladapo JA, Naim A, Lofland JH. The direct healthcare insurer and out-of-pocket expenditures of psoriasis: evidence from a United States national survey. J Dermatolog Treat. 2012;23(4): Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician. 2004;69 (3): Bureau of Labor Statistics, US Department of Labor. Consumer Price Index. Accessed December 8, Villacorta R, Hay JW, Messali A. Cost effectiveness of moderate to severe psoriasis therapy with etanercept and ustekinumab in the United States. Pharmacoeconomics. 2013;31(9): Bhutani T, Wong JW, Bebo BF, Armstrong AW. Access to health care in patients with psoriasis and psoriatic arthritis: data from National Psoriasis Foundation survey panels. JAMA Dermatol.2013; 149(6): Parsi K, Chambers CJ, Armstrong AW. Cost-effectiveness analysis of a patient-centered care model for management of psoriasis. J Am Acad Dermatol. 2012;66(4): Yu AP, Tang J, Xie J, et al. Economic burden of psoriasis compared to the general population and stratified by disease severity. Curr Med Res Opin. 2009;25(10): Fowler JF, Duh MS, Rovba L, et al. The impact of psoriasis on health care costs and patient work loss. J Am Acad Dermatol. 2008;59(5): Lin HC, Lucas PT, Feldman SR, Balkrishnan R. Medication use and associated health care outcomes and costs for patients with psoriasis in the United States. J Dermatolog Treat. 2012;23(3): Staidle JP, Dabade TS, Feldman SR. A pharmacoeconomic analysis of severe psoriasis therapy: a review of treatment choices and cost efficiency. Expert Opin Pharmacother. 2011;12(13): Alora-Palli MB, Brouda I, Green B, Kimball AB. A cost-effectiveness comparison of liquor carbonis distillate solution and calcipotriol cream in the treatment of moderate chronic plaque psoriasis. Arch Dermatol. 2010;146(8): Beyer V, Wolverton SE. Recent trends in systemic psoriasis treatment costs. Arch Dermatol. 2010;146(1): Yentzer BA, Yelverton CB, Simpson GL, et al. Paradoxical effects of cost reduction measures in managed care systems for treatment of severe psoriasis. Dermatol Online J. 2009;15(4): Ahn CS, Gustafson CJ, Sandoval LF, Davis SA, Feldman SR. Cost effectiveness of biologic therapies for plaque psoriasis. Am J Clin Dermatol. 2013;14(4): Leonardi C, Sobell JM, Crowley JJ, et al. Efficacy, safety and medication cost implications of adalimumab 40 mg weekly dosing in patients with psoriasis with suboptimal response to 40 mg every other week dosing: results from an open-label study. Br J Dermatol. 2012;167(3): Liu Y, Wu EQ, Bensimon AG, et al. Cost per responder associated with biologic therapies for jamadermatology.com (Reprinted) JAMA Dermatology June 2015 Volume 151, Number 6 657

8 Clinical Review & Education Review Crohn s disease, psoriasis, and rheumatoid arthritis. Adv Ther. 2012;29(7): Bonafede MM, Gandra SR, Watson C, Princic N, Fox KM. Cost per treated patient for etanercept, adalimumab, and infliximab across adult indications: a claims analysis. Adv Ther. 2012;29(3): Anis AH, Bansback N, Sizto S, Gupta SR, Willian MK, Feldman SR. Economic evaluation of biologic therapies for the treatment of moderate to severe psoriasis in the United States. J Dermatolog Treat. 2011;22(2): Martin S, Feldman SR, Augustin M, Szapary P, Schenkel B. Cost per responder analysis of ustekinumab and etanercept for moderate to severe plaque psoriasis. J Dermatolog Treat. 2011;22 (3): Wu EQ, Feldman SR, Chen L, et al. Utilization pattern of etanercept and its cost implications in moderate to severe psoriasis in a managed care population. Curr Med Res Opin. 2008;24(12): Nelson AA, Pearce DJ, Fleischer AB Jr, Balkrishnan R, Feldman SR. Cost-effectiveness of biologic treatments for psoriasis based on subjective and objective efficacy measures assessed over a 12-week treatment period. JAm Acad Dermatol. 2008;58(1): Delfino M Jr, Holt EW, Taylor CR, Wittenberg E, Qureshi AA. Willingness-to-pay stated preferences for 8 health-related quality-of-life domains in psoriasis: a pilot study. J Am Acad Dermatol. 2008; 59(3): Kimball AB, Guérin A, Tsaneva M, et al. Economic burden of comorbidities in patients with psoriasis is substantial. J Eur Acad Dermatol Venereol. 2011;25(2): Stern RS, Nijsten T, Feldman SR, Margolis DJ, Rolstad T. Psoriasis is common, carries a substantial burden even when not extensive, and is associated with widespread treatment dissatisfaction. J Investig Dermatol Symp Proc. 2004;9(2): Schmitt JM, Ford DE. Work limitations and productivity loss are associated with health-related quality of life but not with clinical severity in patients with psoriasis. Dermatology. 2006;213(2): Lewin Group. The Burden of Skin Diseases: Falls Church, VA: Lewin Group, for the Society of Investigative Dermatology and the American Academy of Dermatology Association; Crown WH, Bresnahan BW, Orsini LS, Kennedy S, Leonardi C. The burden of illness associated with psoriasis: cost of treatment with systemic therapy and phototherapy in the US. Curr Med Res Opin. 2004;20(12): Puig L. Treatment of moderate to severe plaque psoriasis with biologics: analysis of the additional cost of temporary dose escalation vs switch to another biologic after failure of maintenance therapy. Actas Dermosifiliogr. 2014;105(4): NOTABLE NOTES Hippocrates Contributions to Dermatology Revealed Mohammed Alsaidan, MD; Brian J. Simmons, BSc; Fleta N. Bray, BSc; Leyre A. Falto-Aizpurua, MD; Robert Denison Griffith, MD; Keyvan Nouri, MD Although dermatology did not become a medical subspecialty until the end of the 18th century, many concepts regarding dermatological diseases remain as fresh today as when they were first described over 2000 years ago. In the third century BC, the Hippocratic Collection, also known as the Corpus Hippocraticum, gave information about the anatomy and physiology of the skin (eg, the role of perspiration in maintaining homeostasis) and described skin conditions throughout the collection because they were regarded as cutaneous manifestations of systemic diseases. 1,2 For example, Hippocrates noted that clubbed fingernails are associated with underlying pulmonary disease, 2 and that urticaria associated with swollen joints and diarrhea may indicate a worm infestation. 3 Hippocrates also described an association between the onset of guttate psoriasis and a sore throat. As he dealt with anogenital pruritus and ulceration, he was possibly the first person to describe Behcet disease. 3 He described many forms of itching, including itching from icterus. 1 The Corpus Hippocraticum also describes a myriad of cutaneous diseases, which together constitute a short catalog of modern skin diseases, including acne, alopecia areata, freckles, varicose veins, frostbite, various disturbances of the nail, dermatitis, weeping eczema of the scalp, various vesicular, pustularandfissurederuptions, erysipelas, eruptionswithscales and bullae, purulent wounds, secondary infections, anthrax, scabies, condylomas, warts, gangrene, burns, boils, buboes, intertriginous inflammation, scarletfever, aphthousstomatitis, leucoderma, anduniversalexfoliative dermatitis resulting in death. 1 Hippocrates used the word herpetic to creeping eruption and defined lichen as a rough and itchy eruption. His descriptions of skin conditions span the full range of ages from verrucae in children, scrofuloderma in teenagers, to skin cancer in adults. Hippocrates believed that physicians should do the opposite to the body of what was inflicted by the disease, such as applying a drying agent to the moist area and applying an emollient to a dry area. He treated superficial skin tumors by curettage and cautery, using a curette similar to that used today. Hippocrates used clinical observation to make prognosis, for example, Hippocratic facies indicated impending death. 3 Hippocrates was clearly one of the earliest pioneers of medicine and dermatology. However, hisuniquecontributiontodermatologywasovershadowed by his status as the father of medicine and the oath ascribed him. 3 Still, his descriptions of skin diseases and ability to recognize cutaneous manifestations of systemic disease were remarkable and remain a testament to his contributions to the field of dermatology. Author Affiliations: Department of Dermatology, Salman bin Abdulaziz University, Al-Kharj, Saudi Arabia (Alsaidan); Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida (Simmons, Bray, Falto-Aizpurua, Griffith, Nouri). Corresponding Author: Mohammed Alsaidan, MD, Department of Dermatology, Salman bin Abdulaziz University, PO Box 173, Al-Kharj, Riyadh 11942, Saudi Arabia (dr.saidan@hotmail.com). 1. Pusey WA. The History of Dermatology. Vol 1. Springfield, IL: C.C. Thomas; 1933: McCaw IH. A synopsis of the history of dermatology. Ulster Med J. 1944;13(2): Liddell K. Choosing a dermatological hero for the millennium: Hippocrates of Cos ( BC). Clin Exp Dermatol. 2000;25(1): JAMA Dermatology June 2015 Volume 151, Number 6 (Reprinted) jamadermatology.com