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POSTTEST

Easing the Economic and Clinical Burden of Psoriasis and Psoriatic Arthritis: The Role of Managed Care

	The chronic and systemic nature of psoriasis has a significant impact on direct costs, indirect costs, and patient quality of life. Psoriasis is associated with comorbid conditions that add to the burden of the disease, especially in moderate to severe disease. The total estimated annual healthcare burden of psoriasis may be as high as $35.2 billion, with $12.2 billion in direct costs and $23 billion in indirect costs (attributed to reduced health-related quality of life and lost productivity). These costs vary based on the severity of the disease; pharmacy costs account for the majority of the burden, especially in severe disease. Biologic therapies are largely responsible for the pharmacy costs. Approval of biosimilar products in the near future may ease some of this burden for payers and patients, although new agents have also been recently approved, with more in the pipeline.

	The healthcare costs of psoriasis management substantially increase with comorbid conditions, such as heart disease, hyperlipidemia, hypertension, diabetes, and lung disease. These comorbidities also include psychiatric conditions, such as social stigmatization, depression, and suicide. The overall costs associated with comorbidities are estimated to be an additional $22,713 per patient per year. Appropriate treatment selection and timing may curtail the progression of psoriasis, and, as a result, can decrease the economic burden. As treatment options vary based on comorbidities, long-term remission goals, and medication costs, conducting a comprehensive patient assessment is imperative. Drug utilization reviews steered by specialty pharmacists may help reduce costs and improve outcomes by providing treatment monitoring and patient education.

    Psoriasis vulgaris, commonly called psoriasis, is a systemic and chronic immunemediated disorder that is characterized by scaly, erythematous patches, papules, and plaques that are often pruritic.

 Psoriasis is not solely a cosmetic problem. Patients with severe psoriasis die an average of 4 years earlier than controls, with a 50% greater risk of early death (likely due to comorbidities).

 The disfiguring and potentially painful patches resulting from psoriasis can significantly impact quality of life.

 Psoriasis is associated with various comorbidities, significantly adding to the disease burden, especially in moderate to severe disease.

 Available treatment modalities for psoriasis include traditional topical and systemic treatments, newer biologic and biosimilar agents, and phototherapy.

    Innovations in treatment options may help expand the armamentarium available for patients with psoriasis and provide greater efficacy with more tolerable adverse effects (AEs). However, the costs of new medications are typically high. One systematic review of 2013 costs reported that the estimated total cost burden of psoriasis was $35.2 billion, with $12.2 in direct costs and $23 billion in indirect costs (from reduced health-related quality of life and lost productivity).

 These costs may be even higher; another systematic review of 2013 costs reported direct costs of $51.7 billion to $63.2 billion and indirect costs of $23.9 billion to $35.4 billion.

Understanding the Economic Impact of Psoriasis

New and emerging therapeutics, especially in the case of biologic therapeutics, have undoubtedly improved the treatment paradigm because of their increased clinical efficacy. However, these medications are also associated with increased healthcare resource utilization and immediate costs.

A systematic review of selected peer-reviewed articles (N = 91), published between January 2003 and June 2013, examined the clinical, economic, and/or social burdens of psoriasis in the United States. The annual incremental per-patient healthcare cost to payers was estimated to be $1757.4 This did not include the estimated out-of-pocket costs of $527 per patient per year.

     Those with mild disease made up 83% of the population of patients with psoriasis. However, because the treatment modalities recommended are substantially different based on severity, it is important to differentiate between patients with limited disease and those with extensive disease.

The cost amounts varied substantially based on disease severity; total healthcare costs ranged from an average of $1820 for mild disease to $9733 for moderate to severe disease. Accounting for 43% of the cost, outpatient costs were the largest source of expense for treatment of mild disease. Pharmacy costs, which were 10 times greater for moderate to severe versus mild disease, accounted for almost 64% of costs for patients in this population.

	from $8705 to $15,236 and $12,505 to $14,257, respectively. The increased expense for infliximab was attributed to treatment infusion costs (an additional $1013). Cost estimates at 1 year assumed continuous use over the course of a year, although this may not always occur in clinical practice. Taking this into account, infliximab was more cost efficacious over a year (range of $1667 to $2138). Figure 16 shows the total medication costs per treatment period over 1 year.

 Although this analysis of costs was thorough in its inclusion of all available systemic therapies, it did not take into consideration the impact of potential AEs, comorbidity risk reduction, and combination treatments.

		     Psoriasis is not limited to the skin; immune dysregulation and resulting inflammation of psoriasis affects many body systems, and the disease is associated with multiple comorbid conditions, including psoriatic arthritis (PsA), heart disease, stroke, and diabetes.

Psoriasis and its comorbidities impose considerable economic burden. Although the exact cost burden is defined differently

		by various sources, the numbers are staggering. In a systematic review of the annual national burden of psoriasis, including related comorbidities, the cost was estimated at $112 billion in 2013 US dollars.

 Estimates were derived by identifying studies that assessed direct, indirect, intangible, and comorbidity costs of US adults with psoriasis: medical comorbidities contributed $36.4 billion annually, and over a lifetime, a patient with psoriasis would pay $11,498 out of pocket for relief of physical symptoms and emotional health.

	(15.8% vs 9.7%), and lung disease (9.2% vs 6.2%). Patients with psoriasis were more likely to have any medication filled (98.8% vs 76.6%, psoriasis vs control, respectively; odds ratio [OR], 27.5), including antidiabetic drugs (11.3% vs 6.8%; OR, 1.7). They also incurred significantly greater all-cause medical service utilization, as well as greater corresponding costs (

	psoriasis had higher annual total healthcare costs per patient ($22,713 vs $4993; adjusted cost difference [ACD], $18,960; P <.001) than the control group. This was led by significantly higher all-cause medication costs ($14,698 vs $1101; ACD, $13,990; P <.001), the majority of which were attributed to treatment costs for systemic psoriasis therapies ($12,958) that included biologics, nonbiologic agents, and phototherapies (

A similar study was conducted comparing patients with psoriasis and PsA (N = 1230) to psoriasis- and PsAfree matched controls (N =1230), and the results were similar. Patients with moderate to severe psoriasis and PsA had a higher prevalence of comorbidities, healthcare utilization, and costs than matched controls. Patients with psoriasis plus PsA had significantly more related comorbidities than controls, with the 3 most common being hypertension (35.8% vs 23.5%, respectively; OR, 1.9), hyperlipidemia (34.6% vs 28.5%; OR, 1.3), and diabetes (15.9% vs 10.0%; OR, 1.6) (P <.0001 for all comparisons). Compared with controls, patients with psoriasis plus PsA were also more likely to have inpatient admissions (OR, 1.6), emergency department visits (OR, 1.3), and outpatient visits (OR, 62.7) (all P <.05). The adjusted annual cost differences per patient were $23,160 higher for total costs; $17,696 higher for pharmacy costs; and $5077 higher for medical costs for patients with psoriasis plus PsA than for controls (all P <.01).

		     In terms of loss of productivity and decreased quality of life, psoriasis imparts a profound economic impact on patients, payers, and employers.

 A National Psoriasis Foundation survey from 2003 to 2005 of adults older than 30 years found that an adult with psoriasis lost an average of 26 days of work a year due to their illness.

 Those with severe psoriasis were less likely to work full time, and were significantly more likely to report psoriasis as the reason for not working than patients with mild psoriasis (P = .01). Those with severe disease were also significantly more likely to have an income lower than $30,000 compared with patients with mild disease (P = .0002).

	     The social burden of psoriasis in the United States, in terms of productivity loss related to presenteeism (working while sick), was estimated at $4.4 billion annually in a systematic analysis of peer-reviewed articles published between January 2003 and June 2013. In addition, an estimated 16.7% of patients with psoriasis are unemployed because of their disease; this results in estimated lost productivity due to unemployment of $700 per patient and a total of $4 billion annually. The aggregated productivity losses caused by psoriasis (including presenteeism, absenteeism, and unemployment) were $11.2 billion.

	     As with direct costs, these numbers go up substantially when the cost of comorbidities are considered. Another systemic review of studies published between 2008 and 2013 found the estimated indirect costs of psoriasis (absenteeism and lost productivity on the job due to psoriasis and/or its comorbidities) to be upwards of $4000 per person annually (2013 dollars).

		     Psychiatric comorbidities are important among dermatology patients because dermatologic ailments have a substantial impact on body image, a major contributor to depression and suicide. Of the major dermatologic disorders that can be cosmetically disfiguring, patients with psoriasis with extensive disease and residing in an institution had the highest rate of depression—8.9% of outpatients and 10.3% inpatients answered yes to the question, “I often wish I were dead.”

 Low quality of life among patients with psoriasis has repeatedly been seen using the Dermatology Life Quality Index.

 In a recent US survey of dermatologists and patients, increasing severity of psoriasis was associated with increased symptoms, including pain, reduced quality of life, decreased work productivity, and greater impairment.

 Patients with psoriasis have also demonstrated

		significantly lower levels of self-esteem and higher levels of anxiety, loneliness, and social isolation than patients without psoriasis.

 Unfortunately, these psychosocial issues are often under-recognized in patients with the condition. The feelings of depression, suicidal tendencies, and social stigmatization associated with psoriasis should not be trivialized; they should be addressed in a professional setting with appropriate referrals and, when necessary, pharmacotherapy.

 Depression symptoms correlate with PASI scores; clinical improvement of the skin is associated with improved depression.

Quality of life symptoms are often difficult to quantify in economic terms; however, using conservative values for quality-adjusted life-year values, it is estimated that patients with psoriasis experience a $2203 reduction in quality of life per patient per year, accounting for $11.2 billion annually.

Impact of Payment and Reimbursement on Treatment Selection

		     The development of biologic therapies has dramatically affected the treatment of many chronic diseases, including psoriasis.

 Managed care organizations are continuously debating the appropriate use of these injectable drugs because of the associated acquisition costs and administration requirements.

 Important considerations from a managed care perspective include the ability to produce off-treatment remissions, the ability to improve patients’ quality of life, safety and tolerability profiles, and the availability of biosimilars.

			     Appropriate treatment selection and timing may curtail the progression of disease; as a result, the economic burden decreases. As treatment options vary based on the individual patient profile, reviewing the patient’s complete profile is imperative. The selection process must also consider not only the effects on the joints and cutaneous symptoms, but also on the comorbidities. In addition, treatment options for patients experiencing psoriasis versus psoriasis plus PsA may differ.

			     PsA has the potential to result in irreversible, lifelong deformities of the hands and other joints. These patients are at higher risk for developing comorbidities; therefore, they may require more careful selections. Longterm remission goals must be taken into account, as they may overwhelm short-term costs. For example, although MTX and cyclosporine are the most cost-effective pharmacotherapies, their potential toxicities may limit their long-term use.

 The patient’s economic standing should also be considered. Many of the treatment options for psoriasis are cost-prohibitive for patients with private insurance, based on their co-pay; however, the same medication may cost $0 for patients receiving support from Medicaid.

Drug utilization reviews (DURs) conducted by managed care professionals and led by specialty pharmacists can maintain costs by monitoring patient data, ensuring open communication between healthcare providers, and providing educational interventions.

 The complexity of psoriasis and PsA treatment includes disruptions in therapy (dose escalations, dose reductions, switches discontinuations, and restarts), which tend to result in increased overall costs. These disruptions may be curtailed through increased healthcare provider communication through a DUR.

 A retrospective DUR may help change prescribing habits and optimize future drug utilization. Pharmacist-initiated DUR interventions have demonstrated effectiveness in targeted educational initiatives

		on guidelines, treatment options and protocols, and cost management.

 One retrospective analysis of a DUR found that use of automated reminders to physicians about the requirement of prior laboratory testing—based on a drug’s package insert&mdash;curtailed use of the agent in inappropriate patients and improved physician prescribing behavior for the targeted agent.

		cost in these situations, it should be considered that the most severely affected patients may also require the most expensive or creative care.

In 2009, Congress passed the Biologics Price Competition and Innovation Act of 2009 as part of the Affordable Care Act (ACA). Biosimilar agents are similar, but not structurally identical, to a biologic therapy (the reference product). The intent of the law was to establish a balance between innovation and consumer needs and interests.

The law gave the FDA latitude to define the process and standards it uses in approving a drug and to create an abbreviated pathway for approval of biosimilar agents. However, unlike generic products, biosimilar products still have to show clinical trial data for product safety, efficacy, and purity. The difference in the manufacturing processes for biosimilars and the cost of implementing clinical trials makes development of biosimilars more expensive than generic products. Estimates for developing a biosimilar are around $100 million over a 5- to 6-year period compared with $2 to $5 million for a generic drug within 3 years.

Although the constraints of clinical trials and theexpense of the manufacturing process will make costs ofbiosimilars higher than those of generic treatments, they will still remain substantially lower than biologic agents.

Currently, biologic agents, although effective, are expensive and responsible for a significant portion of the cost of psoriasis and PsA treatment. Patents for some biologics used to treat psoriasis are due to expire over the next few years, and it is expected that the biosimilars that will subsequently enter the marketplace will reduce treatment costs associated with the biologics.

		     Because of the administrative resources needed for dosing and administration of biologics, the payment algorithm for these products within the ACA ensures that reimbursement for physicians is the same regardless of the product they prescribe.

However, the government and patients do benefit from the reduced pricing of biosimilars. The Congressional Budget Office estimates that biosimilars could result in $25 billion in savings from 2010 to 2020.

 However, a recent report in the Wall Street Journal suggests that the cost savings may be much less than predicted. Insurers, drug benefit managers, and pharmaceutical industry consultants report that pharmaceutical manufacturers have been increasing the price of biologic therapies about to lose patent protection sometimes 2 to 3 years in advance. Manufacturers of biosimilars are planning on setting the price of these medications just below that of the reference product.

Medicare Part B recently announced a pilot program in certain parts of the country to look at lowering the amounts doctors are paid to administer medications in the office. Currently, Medicare pays doctors the average price of a drug plus 6%, which is thought to incentivize the use of more expensive drugs.

 The program would reduce the 6% add-on to 2.5% plus a flat fee of about $16. This may affect some biologics for psoriasis, such as infliximab, which are administered by the physician.

The substantial direct and indirect costs related to psoriasis and its comorbidities make the cost versus benefit ratio an important consideration in treatment. Although the cost of systemic treatments is increasing (at a much higher rate than inflation),

 the cost of biologic therapies may put effective treatment outside of the reach of many privately insured patients.

		biosimilars may somewhat help reduce this burden on patients. However, the keys to effective management of psoriasis are understanding the role of comorbidities, AEs, and quality of life in the overall cost of treatment, and ensuring long-term remission be taken into account when making decisions based on costs.

     A more extensive study of treatment costs for moderate to severe psoriasis assessed the cost efficacy of currently approved systemic medications by standardizing each therapy based on stimated cost per number needed to treat to achieve a 75% reduction in the Psoriasis Area and Severity Index score (PASI 75). Methotrexate (MTX), cyclosporine, and acitretin required more frequent office visits than phototherapy, as well as more frequent office visits and laboratory costs than biologic medications.

 On a monthly basis, MTX was the least expensive treatment modality to achieve PASI 75, with adjusted monthly costs of $794 to $1503. Considerable variability was observed for the adjusted monthly costs across different studies of the same medications, especially for acitretin, for which the adjusted cost/PASI ranged from $4138 to $14,149, with 34% of patients achieving PASI 75. Infliximab and ustekinumab 90 mg were the most expensive, with adjusted monthly costs ranging

     To understand the full impact of psoriasis and its comorbidities on cost, records over a 5-year period from the OptumHealth Reporting and Insights claims databases were reviewed. A total of 5492 matched pairs of patients with moderate to severe psoriasis and controls were compared for the prevalence of comorbidities, healthcare resource utilization, and costs. Patients with psoriasis were significantly more likely to have comorbidities than the control patients. The 4 most common comorbidities were hyperlipidemia (33.3% vs 27.3%, respectively), hypertension (32.8% vs 23.5%), iabetes

 Evans Dermatology Partners, Austin, Texas.

This activity is supported by educational grants from Lilly and Novartis.

 Dr Evans has disclosed being a volunteer board member for the National Psoriasis Foundation, being a consultant to Celgene; receiving honoraria from About.com, Celgene, and Cigna; and being on speakers’ bureaus for Abbvie and Celgene.

Concept and design, analysis and interpretation of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content.

	1. Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment

 2008;58(5):826- 850. doi: 10.1016/j.jaad.2008.02.039.

	2. Gelfand JM, Troxel AB, Lewis JD, et al. The risk of mortality in patients with psoriasis: results from a population-based study. 

	3. Feldman SR1, Zhao Y, Shi L, Tran MH. Economic and comorbidity burden among patients with moderate-to-severe psoriasis. 

	4. Vanderpuye-Orgle J, Zhao Y, Lu J, et al. Evaluating the economic burden of psoriasis in the United States.

2015;72(6):961-967.e5. doi: 10.1016/j.jaad.2015.02.1099.

	5. Brezinski EA, Dhillon JS, Armstrong AW. Economic burden of psoriasis in the United States: a systematic review. 

. 2015;151(6):651-658. doi: 10.1001/jamadermatol.2014.3593.

	6. D’Souza LS, Payette MJ. Estimated cost efficacy of systemic treatments that are approved by the US Food and Drug Administration for the treatment of moderate to severe psoriasis. 

. 2015;72(4):589-598. doi: 10.1016/j.jaad.2014.11.028.

	7. Christophers E. Comorbidities in psoriasis. 

	8. Feldman SR, Zhao Y, Shi L, Tran MH, Lu J. Economic and comorbidity burden among moderate-to-severe psoriasis patients with comorbid psoriatic arthritis. 

. 2015;67(5):708-717. doi: 10.1002/acr.22492.

	9. Horn EJ, Fox KM, Patel V, Chiou CF, Dann F, Lebwohl M. Association of patient-reported psoriasis severity with income and employment. 

	10. Krueger G, Koo J, Lebwohl M, Menter A, Stern RS, Rolstad T. The impact of psoriasis on quality of life: results of a 1998 National Psoriasis Foundation patient-membership survey.

		11. Schmid-Ott G, Schallmayer S, Calliess IT. Quality of life in patients with psoriasis and psoriasis arthritis with a special focus on stigmatization experience. 

		12. Korman NJ, Zhao Y, Pike J, Roberts J. Relationship between psoriasis severity, clinical symptoms, quality of life and work productivity among patients in the USA. 

		doi: 10.1111/ced.12841. [Epub ahead of print]

		13. Kouris A, Christodoulou C, Efstathiou V, et al. Comparative study of quality of life and psychosocial characteristics in patients with psoriasis and leg ulcers. 

2016;24(2):443-446. doi: 10.1111/wrr.12416.

		14. Lee YW, Park EJ, Kwon IH, Kim KH, Kim KJ. Impact of psoriasis on quality of life: relationship between clinical response to therapy and change in health-related quality of life. 

2010;22(4):389-396. doi: 10.5021/ad.2010.22.4.389.

		15. Elgendia A, Nadab H, Mosbehc AS, Maatoukd M, Abulghanye M, Gulliverf W. Depression over psoriasis: assessment of associated relief by addition of adalimumab for the treatment of psoriasis: observational study (DORADO-Ps). 

 2015;19(1):15-20. doi:10.1016/j.jdds.2014.03.005.

		16. Grabowski HG, Guha R, Salgado M. Regulatory and cost barriers are likely to limit biosimilar development and expected savings in the near future. 

. 2014;33(6):1048-1057. doi: 10.1377/hlthaff.2013.0862.

		17. Rich SJ. Considerations for assessing the cost of biologic agents in the treatment of psoriasis. 

		18. Clark BL, DuChane J, Staskon F, Einodshofer M, Fitzner K, Duncan I. Evaluation of a retrospective drug utilization review program for the treatment of plaque psoriasis: a pilot study. 

 2015; 2(1):1-4. doi:10.4172/2376-0419.1000126.

		19. Feldman SR, Zhao, Y, Navaratnam P, Friedman HS, Lu J, Tran MH. Patterns of medication utilization and costs associated with the use of etanercept, adalimumab, and ustekinumab in the management of moderate-to-severe psoriasis. 

		20. Angalakuditi M, Gomes J. Retrospective drug utilization review: impact of pharmacist interventions on physician prescribing. 

 2011;3:105-108. doi: 10.2147/CEOR.S21789.

		21. Perera PN, Guy MC, Sweaney AM, Boesen KP. Evaluation of prescriber responses to pharmacist recommendations communicated by fax in a medication therapy management program (MTMP). 

		22. Koide D, Ohe K, Ross-Degnan D, Kaihara S. Computerized reminders to monitor liver function to improve the use of etretinate. 

		23. United States Senate. Title VII—Improving access to innovative medical therapies. Subtitle A&mdash;biologics price competition and innovation. FDA website. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ucm216146.pdf. Published March 2010. Accessed March 9, 2016.

		24. Cost estimate: S. 1695 Biologics Price Competition and Innovation Act of 2007. Congressional Budget Office website. www.cbo.gov/sites/default/files/cbofiles/ftpdocs/94xx/doc9496/s1695.pdf. Published June 25, 2008. Accessed March 10, 2016.

		25. Rockoff JD. Knockoffs of biotech drugs bring paltry savings. Wall Street Journal website. http://www.wsj.com/articles/knockoffs-of-biotech-drugs-bring-paltry-savings-1462458209. Published

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		27. Beyer V, Wolverton SE. Recent trends in systemic psoriasis treatment costs. Arch Dermatol. 2010;146(1):46-54. doi: 10.1001/archdermatol.2009.319.

ARTICLES

Managed Care Aspects of Psoriasis and Psoriatic Arthritis

	Over the past several years, an increased understanding of the pathophysiology of psoriasis and psoriatic arthritis (PsA) has led to the development of several new biologic therapies. Appropriate treatment selection and timing may slow, and even halt, the progression of psoriasis and PsA; as a result, it can decrease the economic burden. As treatment options vary based on individual disease characteristics and patient preferences, reviewing the patient’s complete clinical picture is imperative. An updated treatment algorithm, based on patients’ most severe disease domain, is now available to guide the selection of optimal therapy. Special care should be given to patients with both psoriasis and PsA who experience multiple disease domains, a heavy symptom burden, and an increased risk of comorbidities.

Overarching Principles of Psoriasis and Psoriatic Arthritis Treatment

	     Several best practices have emerged to guide the management of patients with psoriasis and psoriatic arthritis (PsA). The current goals for treatment include minimizing disease activity, maintaining functional status, improving quality of life, and preventing or minimizing both disease- and treatment-related complications. The optimal choice of therapy may depend on disease severity, prognostic factors, prior treatment, comorbidities,access to therapy, and patient preferences.Multidisciplinary assessment and management are critical to addressing each aspect of PsA care. In addition, frequent monitoring and treatment adjustments will be necessary to achieve and maintain disease control.

		     Smoking and obesity are examples of risk factors that exacerbate the signs and symptoms of psoriasis and/or PsA and contribute common comorbidities, such as cardiovascular disease.

 In addition, smoking can potentially reduce the effectiveness of anti-tumor necrosis factor-α (TNF-α) therapy.3 Nonpharmacologic interventions, such as smoking cessation, dietary advice, weight loss counseling and physical activity, are important components of comprehensive patient care.

It is essential to diagnose signs or symptoms of psoriatic joint disease early to minimize, even prevent, joint destruction, as psoriatic joint disease usually takes 5 to 12 years to develop after the onset of skin psoriasis.

	     The treat-to-target (T2T) principle of PsA management involves close monitoring and frequent treatment adjustments designed to achieve early and tight control of inflammatory disease activity. In the TICOPA trial, 206 patients with newly diagnosed PsA were randomly assigned to tight control using a T2T strategy or assigned to usual care. In the T2T arm, patients started treatment with methotrexate (MTX) that was escalated to 25 mg after 6 weeks. If patients did not achieve minimal disease activity by week 12, combination disease-modifying antirheumatic drug (DMARD) therapy was started. After

	another 12 weeks, patients with residual disease activity started anti-TNF therapy or switched to an alternate DMARD in combination with MTX. By comparison, patients receiving standard care were seen every 3 months by a rheumatologist but otherwise followed no set treatment protocol.

After 48 weeks, 62% of patients in the T2T arm achieved a 20% improvement from baseline in the American College of Rheumatology response criteria (ACR20) compared with 45% of patients in the standard care group (odds ratio [OR], 1.91; P = .0392). Patients managed with the T2T strategy were also more likely than those in the standard care group to gain control of the skin manifestations of psoriasis (59% vs 33%), defined as a reduction of 75% or more from baseline in the Psoriasis Area and Severity Index score (PASI 75). Although the frequency of adverse events (AEs) increased in the tight control group relative to standard care, most patients tolerated treatment well. The most common AEs were nausea, liver function abnormalities, and respiratory tract infections. These findings support the T2T strategy to improve outcomes across multiple measures in patients with early PsA, including those with skin involvement.

		    Comorbidity screening and management are essential components of psoriasis and of PsA care. Several comorbidities occur with increased frequency in these patients including cardiovascular disease, diabetes, obesity, metabolic syndrome, osteoporosis, liver disease, and depression. Furthermore, patients with psoriasis and PsA are at an increased risk of exhibiting extra-articular manifestations of their underlying autoimmune disease, including inflammatory bowel disease and uveitis. Although the same comorbidity screening and management approaches apply to patients with psoriasis and PsA as to the general population, current guidelines stress the importance of identifying any comorbidities to provide optimal care for these patients.

		     Multiple treatment options, ranging from local therapies (ie, topical medications and phototherapy) to nonbiologic systemic therapies (nonsteroidal anti-inflammatory drugs [NSAIDs] and traditional

		DMARDs) and biologics, are available for patients with psoriasis and PsA. Most clinical studies regarding psoriasis evaluate monotherapy and exclude even potent topical steroids as adjunctive therapy, whereas the majority of patients enrolled in PsA clinical studies will receive maintenance MTX, NSAIDs, and systemic steroids from the outset. In many cases, combination therapy is recommended to enhance treatment efficacy and minimize AEs.

For instance, combining biologic agents such as etanercept or adalimumab with MTX results in greater control of psoriasis disease activity than either

		agent alone. For patients experiencing psoriasis flares, the use of short-term cyclosporine in combination with other systemic or biologic agents is an effective strategy for reducing disease activity Furthermore, the combined use of biologic therapy, especially etanercept and phototherapy, is more effective against psoriatic lesions than either modality used alone.6 Additional combination regimens are reviewed in the following discussion of psoriasis and PsA therapies.

			      Topical medications are the first-line treatment option for the majority of patients with psoriasis who have limited disease, which is often defined as up to 5% of the body surface area (BSA). In addition, topical therapies continue to be used in adjunct with systemic therapies in patients with extensive disease (>5% BSA) who require more aggressive intervention. Options for topical treatment include emollients, topical corticosteroids, topical vitamin D analogs (eg, calcipotriene/calcipotriol, calcitriol, and tacalcitol), retinoids (eg, tazarotene), and calcineurin inhibitors (eg, topical tacrolimus 0.1% and

			pimecrolimus 1%). In addition, a combination of a potent topical steroid and a vitamin D analogue in one preparation has shown to be effective. The amount of topical medication required to treat various BSA percentages can be gauged by the “fingertip unit” method, with 1 fingertip unit corresponding to approximately 2% BSA (

); this corresponds to approximately 500 mg.

     Multiple factors influence the choice of topical therapy, including body site, thickness and scaling of the psoriasis lesions, patient age, costs, and patient preferences. Poor adherence to topical medications is a major barrier to successful psoriasis treatment, with up to 40% of patients with psoriasis reporting nonadherence due to inconvenience, time constraints, frustration with medication efficacy, unclear instructions, and fear of AEs.

Therefore, the successful use of topical medications requires a particular emphasis on patient education and counseling.

	     Ultraviolet (UV) irradiation controls psoriatic skin lesions by targeting hyperproliferative epidermal cells and T-cells.

 Phototherapy is recommended as first-line therapy for moderate to severe psoriasis when skin involvement is too extensive for topical therapy alone. In addition, phototherapy is an appropriate treatment strategy for patients with limited skin involvement, but debilitating symptoms, such as those with severe psoriasis of the palms, soles, and scalp. For patients with PsA, phototherapy is also used to manage the cutaneous manifestations of psoriatic disease.

 Phototherapy is also appropriate in patients with contraindications to systemic treatment, such as women who are pregnant.

Multiple phototherapy regimens are currently used in the outpatient setting.9 Pretreatment with topical or oral photosensitizing agents, such as psoralen, enhances the cytotoxic effects of UVA therapy and further inhibits epidermal cell proliferation. Photochemotherapy with oral psoralen and UV-A radiation (PUVA) can lead to dramatic improvements in psoriatic skin lesions.

However, PUVA is less tolerated than UV-B-based phototherapy, with an increased risk of nonmelanoma skin cancer after 200 treatments. Phototherapy is costeffective for controlling psoriatic skin lesions but is less convenient for patients because of travel time and costs associated with absence from work.

 Thus, several home phototherapy units are available and prescribed under the guidance of dermatologists.

      NSAIDs play a central role in reducing inflammation and discomfort, particularly in patients with PsA with prominent axial disease, enthesitis, and dactylitis.

	     Traditional DMARDs, including MTX, sulfasalazine, leflunomide, and cyclosporine, are frequently used as first-line therapies for patients with PsA.

 In addition, these agents also form the backbone of many combination regimens for both skin and joints, such as MTX plus phototherapy for skin psoriasis, MTX plus biologic agents for skin and joints, or targeted small-molecule inhibitors. MTX is also the most commonly used systemic therapy worldwide for patients with moderate to severe psoriasis.

 Although highly effective as short-term monotherapy for skin psoriasis, cyclosporine is not nearly as effective for PsA. Conversely, neither sulfasalazine nor leflunomide, while helpful as adjunctive therapies for PsA, has an appreciable effect on skin psoriasis.

Prior to initiating MTX, patients should be evaluated for potential drug—drug interactions (eg, MTX and sulfonamide-derived drugs), risk factors, and contraindications. Of note, MTX is absolutely contraindicated during pregnancy and breastfeeding. In the absence of contraindications, MTX is usually started at a dose of 10 to 15 mg/week and titrated to a maximum recommended dose of 25 mg/week. Although most patients begin treatment with oral MTX, parenteral administration is an option for patients who develop gastrointestinal intolerance, for those with an inadequate response to maximally titrated oral therapy, and in cases with high risk of nonadherence and/or dosing errors.

 In addition, MTX as monotherapy is highly effective in less than half of patients with psoriasis. The addition of oral folic acid (1-5 mg daily) is essential with MTX therapy to minimize adverse effects.

		      The development of biologic therapies targeting key molecules involved in disease pathogenesis has revolutionized the treatment of moderate to severe psoriasis and PsA.

 Biologics can be classified as large molecules (eg, monoclonal antibodies), which must be given by injection or infusion, and small molecules, which are given orally.16 The contraindications, precautions, and

		common AEs of each treatment option should be considered when selecting biologic therapy for patients with psoriasis and PsA (

 Long-term postmarketing surveillance data confirmed the safety of anti-TNF therapy in patients with psoriasis, with no new safety signals emerging after 5 years of treatment.

		     New insights into the pathogenesis of psoriasis and PsA led to the identification of novel therapeutic targets across different biologic pathways, including interleukin (IL)-12, IL-23, and IL-17. Ustekinumab, a fully human monoclonal antibody directed against IL-12/23, was the first of these novel targeted therapies to be approved for the treatment of psoriasis and PsA.

 In 2 phase 3 trials in patients with psoriasis, the majority of patients treated with ustekinumab 45 mg or 90 mg achieved a PASI 75 response after 12 weeks of therapy compared with less than 4% of patients given placebo.

Ustekinumab is also effective in patients with moderate to severe psoriasis who had an inadequate response to prior TNF inhibition, with approximately 50% of patients achieving a PASI 50 response or better within 28 weeks of switching to ustekinumab.

Ustekinumab demonstrated clinical efficacy in PsA in 2 phase 3 randomized trials. In the first randomized, placebo-controlled, phase 3 trial of patients with active PsA (N = 615), 42% and 50% of patients treated with ustekinumab 45 mg or 90 mg, respectively, achieved an ACR20 response after 24 weeks compared with 23% of patients in the placebo group (P <.001).

 In another phase 3 trial of patients with active PsA despite prior treatment with conventional DMARD or biologic therapy (N = 312), treatment with ustekinumab 45 mg or 90 mg was shown to significantly improve quality of life and physical

		functioning in addition to reducing the clinical signs and symptoms of PsA compared with placebo.

	      Five TNF inhibitors are currently available for the treatment of PsA: etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. Most anti-TNF therapies are available for subcutaneous injection, except infliximab, which is given by intravenous infusion.

 Therapies targeting TNF reduce the signs and symptoms of joint disease in the majority of patients with PsA.

TNF inhibitors are also effective at addressing extra-articular manifestations of PsA, including skin involvement, axial disease, enthesitis, and dactylitis.

 Long-term treatment with anti-TNF agents also reduces the need for glucocorticoid therapy for PsA over time. In one study of biologic-naïve patients with PsA (N = 420), 49.6% were taking glucocorticoids at baseline. After starting anti-TNF therapy (adalimumab, etanercept, or infliximab), the rate of glucocorticoid use decreased to 36.5% at 2 years, 29.9% at 3 years, and 22.6% at 4 years. Moreover, among patients taking prednisone, the average daily dose significantly decreased from 5.6 mg at baseline to 4 mg at 4 years.

Adalimumab, etanercept, and infliximab are also approved for the treatment of psoriasis. In an analysis of real-world registry data (N = 6059), 57% of patients with moderate to severe psoriasis achieved clear/almost clear status by Physician’s Global Assessment (PGA) after 12 months of treatment with adalimumab; this increased to 65% of patients after 60 months of treatment.

 In another observational registry study of etanercept in patients with moderate to severe psoriasis (N = 2510), 51% of patients achieved clear/almost clear status by month 6 of treatment and remained stable throughout 5 years of	

		treated with etanercept (P <.001 for each comparison with secukinumab). Moreover, 51% to 65% of patients treated with secukinumab achieved a PASI 75 response at week 12 compared with less than 3% of patients in the placebo group and 27% of those treated with etanercept (P <.001 for each comparison with secukinumab). In both trials, the rate of infection in the secukinumab group was higher than with placebo and similar to that with etanercept.36 In early 2015, secukinumab became the first IL-17A inhibitor approved for the treatment of moderate to severe plaque psoriasis.

		     In 2016, the FDA expanded the secukinumab indication to include PsA treatment based on findings from the phase 3 FUTURE 1 and FUTURE 2 trials.

 In the FUTURE 1 trial (N = 606), 50.0% and 50.5% of patients treated with secukinumab 150 mg or secukinumab 75 mg, respectively, achieved an ACR20 response by week 24 compared with 17.3% of patients in the placebo group (P <.001 for both comparisons).

 In a follow-up analysis of the FUTURE 1 trial, secukinumab was also associated with a significant reduction in radiographic progression of structural joint damage relative to placebo through 52 weeks of treatment. The FUTURE 2 trial compared 3 doses of secukinumab (300, 150, and 75 mg) with placebo in 397 patients with PsA.38 After 24 weeks, the ACR20 response rates were significantly higher across all secukinumab dosing groups compared with placebo. In particular, patients were 6-fold more likely to achieve an ACR20 response in the 2 highest-dosing groups, secukinumab 300 mg (54%; OR, 6.8; P <.0001) or secukinumab 150 mg (51%; OR, 6.5; P <.0001) than with placebo (15%).39 In both trials, secukinumab was associated with an increased risk of

			     Ixekizumab is the most recent (2016) anti—IL-17A monoclonal antibody to join the psoriasis treatment armamentarium. Treatment with ixekizumab was initially evaluated in a dose-finding phase 1 trial of 40 patients with psoriasis. Across all dosing groups (5, 15, 50, and 150 mg), ixekizumab demonstrated significant dosedependent reductions in the clinical presentation of psoriasis, including reductions in keratinocyte proliferation and hyperplasia. Patients treated with the 2 highest doses of ixekizumab (50 mg and 150 mg) achieved near normalization of skin after 6 weeks of treatment, confirmed by biopsy analysis.40 Subsequent trials with ixekizumab showed greater efficacy than placebo and etanercept, with results seen as early as the first week on ixekizumab treatment. In addition, rapid and significant improvements in itch severity and quality of life were observed.

In 2016, the FDA approved ixekizumab for the treatment of moderate to severe plaque psoriasis based on findings from the UNCOVER-1, UNCOVER-2, and UNCOVER-3 trials, which evaluated ixekizumab in patients with moderate to severe plaque psoriasis (N = 3866). Overall, 87% to 90% of patients achieved a PASI 75 response by week 12, which was sustained through 60 months of treatment. The most common AEs were nasopharyngitis, upper respiratory tract infection, injection-site reaction, and headache.

 Ixekizumab was also shown to significantly improve short- and long-term work productivity, which is an important end point for patients that influences the cost burden of psoriasis.

	     The IL-17 signaling pathway plays an important role in the pathogenesis of psoriasis. IL-17 is a proinflammatory cytokine that acts on a wide range of cells, including keratinocytes. It is richly expressed in psoriatic skin lesions and in the synovial fluid of patients with PsA. Targeted therapies that block the activity of IL-17 show potent efficacy in controlling the underlying disease activity associated with psoriasis and PsA.

Two subsequent randomized, double-blind, phase 3 trials established the safety and efficacy of secukinumab in plaque psoriasis. Patients with moderate to severe psoriasis (N = 2044) were randomly assigned to treatment with subcutaneous secukinumab (150 or 300 mg once weekly for 5 weeks, then every 4 weeks), placebo, or etanercept (50 mg twice weekly for 12 weeks, then once weekly) for 52 weeks. After 12 weeks, 67% to 81% of patients in the secukinumab groups experienced either clear or almost clear skin compared with less than 5% of patients in the placebo group and 44% of patients	

Ixekizumab is currently under evaluation for the treatment of PsA. One recent phase 3 trial compared ixekizumab 80 mg every 2 weeks or every 4 weeks, adalimumab 40 mg every 2 weeks, and placebo in patients with PsA who were naïve to biologic therapy (N = 417). After 24 weeks, 58% to 62% of patients treated with ixekizumab achieved an ACR20 response compared with 30% of those in the placebo group (P <.001). In the adalimumab group, 57% of patients achieved an ACR20 response. These findings support the potential role of ixekizumab given every 4 weeks in the treatment of active PsA, which represents improved convenience for patients when compared with standard biweekly treatment.

		     Whereas secukinumab and ixekizumab neutralize IL-17A, brodalumab blocks its receptor (IL-17RA). In a phase 1 proof-of-concept study, brodalumab showed a dose-dependent improvement in the clinical signs and symptoms of moderate to severe plaque psoriasis. Brodalumab also demonstrated a rapid reversal of adverse gene expression and histopathologic abnormalities, supporting the rationale for IL-17A—receptor blockade in psoriasis.

 Brodalumab has been shown to significantly improve the clinical signs and symptoms of psoriasis and PsA.

 However, the clinical development of brodalumab has been complicated by safety concerns, particularly rare reports of suicidal ideation in these patient populations.

 The Biologics License Application for brodalumab in moderate to severe psoriasis is currently under review with the FDA; it has an expected action date of November 16, 2016.

     Small molecular weight inhibitors of inflammatory mediators are another option for targeting the pathogenesis of psoriasis and PsA. With oral bioavailability, this therapeutic class represents improved convenience and the potential for improved adherence among patients with reservations regarding injectable therapy.

		     Apremilast is an oral inhibitor of phosphodiesterase 4 that indirectly down-regulates the inflammatory response by enhancing the expression of anti-inflammatory cytokines while suppressing the activity of pro-inflammatory cytokines.

 In March 2014, apremilast became the first oral biologic drug approved for the treatment of active PsA. Later that year, in September 2014, the FDA expanded the indication for apremilast to include treatment of moderate to severe plaque psoriasis in patients for whom phototherapy or systemic therapy is appropriate.

The approval of apremilast in PsA and plaque psoriasis was based on the phase 3 PALACE and ESTEEM clinical trial programs.

PALACE 1 evaluated apremilast in 504 patients with active PsA despite standard treatment with synthetic DMARDs or biologic therapy. At week 16, approximately 30% and 40% of patients treated with apremilast 20 or 30 mg twice daily, respectively, achieved an ACR20 response compared with approximately 20% of those in the placebo group (P <.001).

 The ESTEEM 1 trial compared apremilast 30 mg twice daily or placebo in 844 patients with moderate to severe plaque psoriasis. After 16 weeks, 33% of patients in the apremilast group achieved a 75% or greater reduction in the PASI score compared with 5% of patients in the placebo group (P <.0001).

 Focusing on concomitant PsA and psoriasis, the PALACE 3 trial evaluated apremilast in 505 patients with PsA and current skin involvement. Treatment with apremilast 20 or 30 mg twice daily was associated with clinically meaningful improvements in both PsA and psoriasis measures by week 16, and sustained improvements continued through week 52.

 Apremilast was well tolerated and exhibited a highly acceptable safety profile. Up to 17% of patients develop gastrointestinal AEs in the first month of therapy.

 However, no laboratory monitoring of patients on apremilast is required.

			     Tofacitinib is a novel oral Janus kinase (JAK) inhibitor currently approved for the treatment of rheumatoid arthritis; it shows promising activity in both psoriasis and PsA.

 In a placebo-controlled phase 2 trial of patients with moderate to severe psoriasis (N = 197), twice-daily treatment with tofacitinib 2, 5, or 15 mg was associated with significant dose-dependent improvements in multiple patient-reported outcomes, including dermatologyrelated quality of life, itch severity, and Short Form-36 psychological and physical domains.

Two recent identical phase 3 trials confirmed the safety and efficacy of tofacitinib in patients with psoriasis. In total, 1861 patients were randomly assigned 2:1 to treatment with oral tofacitinib (5 or 10 mg) or placebo twice daily. After 28 weeks, 55.6% and 68.8% of patients in the tofacitinib 5-mg and 10-mg groups, respectively, achieved a PASI 75 response; 54.7% and 65.9% of patients, respectively, achieved clear/almost clear status by PGA. Treatment efficacy was sustained in most patients through 24 months. The most common AEs were nasopharyngitis (18.8%) and upper respiratory tract infection (12.6%). Overall, 10.1% of patients developed serious AEs, and 10.7% discontinued treatment due to AEs.

	serious AEs and 1% to 3% of patients discontinuing treatment due to AEs.

In patients with PsA, tofacitinib appears to reduce synovial inflammation and other markers of PsA disease activity.

 In a randomized, double-blind, phase 3 trial of patients with psoriasis and/or PsA (N = 99), treatment with tofacitinib 5 mg or 10 mg twice daily was associated with high response rates, as measured by PASI 75 response (63% and 73%, respectively) and a clear/almost clear PGA response (67% to 68%). In addition, all patients with PsA (N = 12) achieved an ACR20 response by treatment week 12. Four patients (4.3%) developed serious AEs, including 3 cases of herpes zoster infection.59 Overall, these findings support the potential therapeutic role of JAK inhibition in patients with PsA (similar to rheumatoid arthritis, for which tofacitinib FDA approved). A topical formulation of tofacitinib ointment is currently under development for the treatment of chronic plaque psoriasis.

Treatment Selection in Practice: 2016 GRAPPA PsA Treatment Algorithm

     In a phase 3 noninferiority trial, tofacitinib 10 mg twice daily was noninferior to etanercept 50 mg twice weekly and superior to placebo in terms of PASI 75 response and clear/almost clear PGA response in patients with moderate to severe plaque psoriasis. The safety analysis showed similar AE rates at 12 weeks in patients treated with tofacitinib or etanercept, with 2% of patients developing

     In 2016, the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) published updated guidelines on the management of patients with PsA, including those with psoriasis. The new guidance defines the 6 major domains of PsA: peripheral arthritis, axial disease, enthesitis, dactylitis, skin involvement, and nail disease. While many patients with PsA exhibit multiple manifestations, the selection of therapy should be driven by the most severe component of each patient’s clinical presentation (

	     Traditional DMARDs and biologic therapies are strongly recommended for the treatment of PsA. In particular, biologics should be initiated early in patients with poor prognostic factors, such as high inflammatory markers and multiple active joints. For patients with an inadequate response to their first biologic therapy, switching to a second biologic agent is recommended. The GRAPPA guideline supports the conditional use of NSAIDs and corticosteroids to control the signs and symptoms of PsA but also indicates that these agents should be used with caution due to the potential for AEs. If needed, corticosteroids should be given in the lowest doses (eg, <7.5 mg/day) and for short periods of time to provide symptomatic control.

		     Given the lack of clinical trial data in PsA-specific axial disease, the GRAPPA recommendations rely on experience in ankylosing spondylitis. Appropriate firstline therapy for axial disease can include NSAIDs, sacroiliac injections, and physiotherapy. However, traditional DMARDs show poor efficacy against axial manifestations. Therefore, patients with PsA with predominant axial disease who require treatment intensification should consider early initiation of anti-TNF therapy.

	     Standard first-line treatment for enthesitis involves NSAIDs. As with axial disease, there is a lack of evidence to support the use of DMARDs to treat enthesitis. Therefore, for patients with an inadequate response to NSAIDs alone, biologics are the recommended second-line therapies. In that group, TNF inhibitors and ustekinumab appear to be highly effective in reducing the tendon and ligament inflammation characteristic of enthesitis. Preliminary evidence also supports the use of secukinumab and apremilast to treat enthesitis in patients with PsA.

Over the past several years, an increased understanding of the pathophysiology of psoriasis and psoriatic arthritis has led to the development of several new biologic therapies.

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