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Part 1: Targeting The IL-23/Th17 Pathway

The treatment of psoriasis is changing, thanks to a growing understanding that it is a disease of systemic inflammation.1,2 In this regard, drug candidates targeting the interleukin-23 (IL-23) and type-17 helper (IL-23/Th17) T-cell pathway ap-pear particularly promising, offering high rates of clearance or near-clearance of psoriatic lesions.3–5 Along with their role in treating psoriasis, ustekinumab (Stelara, Janssen) and the tumor necrosis factor-alpha (TNF-a) inhibitors, in particular, are helping physicians target cardiovascular disease,6–8 one of the many known comorbidities of psoriasis.

In the pathogenesis of psoriasis, the IL-23/Th17 pathway has been shown to be crucial in the immune system. Andrew Blauvelt, MD, MBA, president of the Oregon Medical Research Center, explained during a telephone interview with P&T:

Its normal function is to fight skin and mucous membrane infections. In particular, IL-17 has been shown to be importantly involved in control of cutaneous infections caused by Candida albicans and Staphylococcus aureus. Both mice and humans with deficiencies in IL-17 can develop chronic infections with these organisms. By contrast, this pathway is overactive in psoriasis. In other words, there are high levels of IL-23, which stimulate proliferation and high numbers of Th17 cells. These cells, in turn, produce excess amounts of IL-17A (a protein just downstream of IL-23), which stimulates keratinocyte activation and proliferation.

NewBiologicsAimtoImproveSafetyandEfficacyAfter 12 weeks of ustekinumab therapy, the first biologic drug

approved by the FDA to target proteins in this pathway, 70% of patients reach Psoriasis Area and Severity Index (PASI) 75, or a 75% reduction in clinical severity.9,10 The following biologic drugs under development also target some portion of the IL-23/Th17 pathway, said Dr. Blauvelt:

•Secukinumab (Novartis) and ixekizumab (Eli Lilly) inhibit IL-17A (Figure 1). Results of the FIXTURE (Full year Investigative eXamination of secukinumab vs. eTaner-cept Using 2 dosing Regimens to determine Efficacy in psoriasis) phase 3 study were announced in October. A Study of ixekizumab in Participants With Active PsorIatic ArthRITis (SPIRIT–P1), in phase 3, is ongoing.

•In late phase 3 trials, brodalumab (Amgen) targets IL-17 receptors, which reside on keratinocytes.

•Tildrakizumab (Merck) and guselkumab (Janssen) target IL-23. Tildrakizumab is in early phase 3 clinical trials. A phase 2 study of guselkumab was recently completed.

Collectively, the new IL-23/Th17 blockers have demonstrated PASI 75 rates of more than 80% in published phase 2 studies,3–5 said Dr. Blauvelt, who has evaluated more than 130 patients who received these drugs. For IL-17 blockers in particular, he added, “The rates of PASI 90 and PASI 100 are also very high.” Therefore, he said, complete clearance or near-clearance of psoriatic lesions soon may be a reasonable therapeutic target, with no apparent sacrifice in short-term safety.

Earlier-generation TNF inhibitors, such as etanercept (Enbrel, Amgen/Pfizer) and adalimumab (Humira, Abbott), he said, may be associated with more adverse effects, such as systemic infections, because they target patients’ immune systems more broadly. With time, he added, more complete long-term safety profiles will be available for the newer biologic agents.

“However, it is also possible that the older biologics have [produced] more adverse reactions noted simply because they’ve been around longer,” said Steven R. Feldman, MD, PhD, Professor of Dermatology, Pathology, and Public Health Sciences at Wake Forest University School of Medicine (in Winston-Salem, North Carolina) in a telephone interview.

Dr. Blauvelt said that so far, new third-generation biologics appear both more efficacious and safe, because they selec-tively target the immune system that resides within the skin. Nevertheless, “long-term safety with these drugs remains to be determined.”

In a 5-year safety study, ustekinumab was associated with no increase in cancers or serious infections.11 The new biologics tar-get the same pathway but in a more focused fashion, he added.

He said, “I believe they are very promising. I’m not worried as much about safety with third-generation biologics as I am about loss of efficacy over time, which we see with all biologic drugs.”

TNFBlockersBattleComorbiditiesTargeting the immune system more broadly could confer

advantages. Specifically, TNF inhibitors appear to improve some of the comorbidities of psoriasis.

Regarding psoriatic arthritis, for which the FDA approved ustekinumab in September 2013, two phase 3 clinical trials showed that after 24 weeks of therapy, the proportion of patients who achieved a 20% reduction in American College of Rheumatology criteria (ACR 20) were 42% and 44% at the 45-mg dose, and 44% at the 90-mg dose.12 The proportions of patients achieving ACR 20 response levels in phase 3 trials of adalimumab and etanercept at week 24 were 57% and 50%, respectively.13,14

In a seminal report, severe psoriasis proved to be an in-dependent risk factor for heart disease.15 Approximately 20 subsequent reports have confirmed the link between psoriasis

AdvancesinPsoriasisTreatmentExpertsCommentonRecentDevelopments

Peter Sonnenreich, MA

Mr. Sonnenreich is a contributing writer for P&T. He is based in Bethesda, Maryland.

Disclosure: The author reports that he has no commercial or financial relationships in regard to this article.

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and cardiovascular disease,16–19 said Dr. Blauvelt. In one study, positron emission tomography (PET) was used to document the presence of widespread systemic inflammation in patients with psoriasis confined to the skin.1 Dr. Blauvelt explained:

This is significant, because there are indications coming from the rheumatologic literature that TNF-blocker therapy can decrease the incidence of cardiovascular disease in patients with rheumatoid arthritis.6 A couple of early studies suggest that the same thing oc-curs in patients with psoriasis who are treated with TNF inhibitors.7

For example, initial results from the 12,000-patient PSOriasis Longitudinal Assessment and Registry (PSOLAR) study sug-gest that patients treated with TNF inhibitors or ustekinumab experience fewer heart attacks versus those using other sys-temic treatments.8

In the first large prospective, matched-cohort study to examine disease associations of psoriasis over time—Incident Health Outcomes and Psoriasis Events (iHOPE)—more severe psoriasis correlated with a higher risk of major medical problems.20 Senior study author Joel M. Gelfand, MD, told P&T in a telephone interview:

“As patients go from very limited to very severe disease, we observed a clear dose response.” Dr. Gelfand is Associate Professor of Dermatology and Epidemiology at the University of Pennsylvania Perelman School of Medicine in Philadelphia.

For example, the likelihood of heart attacks, strokes, and peripheral or cerebral vascular disease for patients with limited psoriasis—less than 2% body surface area (BSA) affected—was 14%, compared with 80% for patients with psoriasis that affected more than 10% of BSA. A similar dose response occurred for diabetes, and—for the first time—its complications, including eye disease and neuropathy, he said. Dose responses also emerged for chronic obstructive pulmonary disease, kidney disease, and peptic ulcers, comorbidities that few prior studies have addressed, Dr. Gelfand pointed out. For the first time, these results allow psoriasis patients and their caregivers to determine the likelihood of such comorbidities developing, he said.

“Those with 3% to 10% BSA involvement or higher start having more significant associations with health problems. Therefore, it’s important for these patients to undergo appropri-ate medical screenings, eat a healthy diet, exercise, maintain a healthy body weight, and avoid smoking.”

As for physicians and health care insurance plans, Dr. Gelfand said:

The major lesson is to ensure that our patients with psoriasis— especially those with more severe disease—undergo screening and treatment for major, modifiable cardiovascular risk factors. These data have implications for how we monitor people. Similarly, the emerging data for kidney disease suggest that we more care-fully screen patients by using blood and urine analysis and that we carefully consider the use of nephrotoxic medications in this at-risk population. A more comprehensive medical screening is indicated for these patients.

In the ongoing randomized Vascular Inflammation in Psoriasis (VIP) trial, investigators have assigned patients to receive adalimumab, phototherapy, or placebo for 12 weeks before crossing over to open-label adalimumab. This way, said Dr. Gelfand, “We’ll see what effects prolonged suppression of TNF has on the vasculature. The purpose is to rigorously determine whether systemic treatment with a TNF inhibitor would suppress vascular inflammation, a known predictor of future vascular problems.”

Because phototherapy treats only locally, he added, “it might not have an effect. But it may—we don’t know.”

Scheduled for completion in 2017, the VIP study also will incorporate sophisticated measures of lipid metabolism such as high-density lipoprotein (HDL) function and low-density lipoprotein (LDL) particle size and density.

Overall, said Dr. Feldman, what such studies reveal regarding inflammatory disease may not only improve patients’ length and quality of life, but they could also affect how patients, insurers, and the government view psoriasis treatments.

“Soon we are going to be living in a world where showing that your drug prevents the heart attacks that are associated with psoriasis is going to be a major advantage,” he said.

For dermatologists, added Dr. Blauvelt, the growing recogni-tion of psoriasis as a systemic condition “probably will increase the pressure to treat with more systemic therapies.”

References1. Mehta NN, Yu Y, Saboury B, et al. Systemic and vascular inflam-

mation in patients with moderate to severe psoriasis as measured by [18F]-fluorodeoxyglucose positron emission tomography/computed tomography (FDG–PET/CT): A pilot study. Arch Dermatol 2011;147(9):1031–1039.

2. Kagami S, Rizzo HL, Lee JJ, et al. Circulating Th17, Th22, and Th1 cells are increased in psoriasis. J Invest Dermatol 2010; 130(5):1373–1383.

3. Leonardi C, Matheson R, Zachariae C, et al. Anti–interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med 2012;366(13):1190–1199.

4. Rich P, Sigurgeirsson B, Thaci D, et al. Secukinumab induction and maintenance therapy in moderate-to-severe plaque psoriasis: A randomized, double-blind, placebo-controlled, phase II regimen-finding study. Br J Dermatol 2013;168(2):402–411.

5. Papp KA, Leonardi C, Menter A, et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med

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Figure 1 Secukinumab and ixekizumab selectively block interleukin (IL)-17. Th17 = T helper 17 cell; TRL2 = toll-like receptor 2. (Courtesy of Dr. Andrew Blauvelt.)

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2012;366(13):1181–1189.6. Greenberg JD, Furer V, Farkouh ME. Cardiovascular safety of

biologic therapies for the treatment of RA. Nat Rev Rheumatol 2011;8(1):13–21.

7. Wu JJ, Poon KY, Channual JC, Shen AY. Association between tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis. Arch Dermatol 2012;148(11):1244–1250.

8. Papp KA, Strober B, Augustin M, et al. PSOLAR: Design, utility, and preliminary results of a prospective, international, disease-based registry of patients with psoriasis who are receiving, or are candidates for, conventional systemic treatments or biologic agents. J Drugs Dermatol 2012;11(10):1210–1217.

9. Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 2008; 371(9625):1665–1674. Erratum, Lancet 2008;371(9627):1838.

10. Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 2008; 371(9625):1675–1684.

11. Papp KA, Griffiths CE, Gordon K, et al. Long-term safety of ustekinumab in patients with moderate-to-severe psoriasis: Final results from 5 years of follow-up. Br J Dermatol 2013;168(4):844–854.

12. Stelara (ustekinumab), prescribing information. Horsham, Pa.: Janssen Biotech, Inc.; 2012.

13. Humira (adalimumab), prescribing information. North Chicago, Ill.: Abbott; January 2013.

14. Enbrel (etanercept), prescribing information. Thousand Oaks, Calif.: Amgen/Pfizer, 1998–2013.

15. Gelfand JM, Niemann AL, Shin DB, et al. The risk of myocardial infarction in patients with psoriasis. JAMA 2006;296:1735–1741.

16. Friedewald VE, Cather JC, Gelfand JM, et al. AJC editor’s consensus: Psoriasis and coronary artery disease. Am J Cardiol 2008;102(12):1631–1643.

17. Malerba M, Gisondi P, Radaeli A, Girolomoni G. Psoriasis and risk of myocardial infarction. JAMA 2007;297(4):361–362; author reply, 362–363.

18. Tobin AM, Hughes R, Hand EB, et al. Homocysteine status and cardiovascular risk factors in patients with psoriasis: A case– control study. Clin Exp Dermatol 2011;36(1):19–23.

19. Doukaki S, Caputo V, Bongiorno MR. Psoriasis and cardiovascular risk: Assessment by CUORE project risk score in Italian patients. Dermatol Res Pract, September 8, 2013 (online).

20. Yeung H, Takeshita J, Mehta NN, et al. Psoriasis severity and the prevalence of major medical comorbidity: A population-based study. JAMA Dermatol 2013;149(10):1173–1179.

Part 2: Improving Patient Compliance And Outcomes in Psoriasis

Keys to improving patient adherence to psoriasis treatment include forging strong relationships with patients (and when necessary, their caregivers) and making treatments easy to use, said Steven R. Feldman, MD, PhD, at the American Academy of Dermatology Summer Academy in New York from July 31 through August 4, 2013. The gathering drew more than 3,300 attendees, including more than 2,000 dermatologists and other medical personnel. Along with the diagnosis and treatment of skin, hair, and nail problems, key themes included the need to better communicate the role of dermatologists and the scope of their practices to the public. Dr. Feldman is Professor of Dermatology, Pathology, and Public Health Sciences at Wake Forest University School of Medicine in Winston-Salem.

The main reason that psoriasis treatments fail is that patients

simply don’t use them, Dr. Feldman said. “Many patients don’t even fill their prescriptions (i.e., primary nonadherence).”

A study from Denmark found that only half of patients with psoriasis had filled their prescriptions within 1 month of receiv-ing them—the lowest compliance rate among several dermato-logical diagnoses, including skin infections, acne, and eczema.1

Conversely, Dr. Feldman said, involving patients in treatment decisions, such as the choice of a topical vehicle, gives them a stake in the outcome:2 “The best vehicle is the one that a patient will use.”

Psoriasis does not require moisturizing ointments, he ex-plained, just an application of a topical steroid in whatever form (ointment, cream, solution, or foam) a patient prefers.

Favorable compliance rates are typically achieved in clinical trials because patients are highly motivated. They are being paid (and they know they are being monitored) as part of the study, he said. To counter these biases, Dr. Feldman and colleagues performed a study involving children with atopic dermatitis whose parents did not know they were enrolled in a study. Although the patients were instructed to use 0.1% tri-amcinolone twice daily, they applied the drug at only 32% of the recommended doses, as tracked by electronic medication caps.3

Even biologic drugs for psoriasis, many of which are admin-istered in doctors’ offices, can be associated with poor compli-ance. In a recent trial of adalimumab (Humira), investigators instructed patients to self-inject a second dose 7 days after the first day and then to re-inject the medication every 14 days thereafter.4 Excluding the second dose, the actual number of days between doses ranged from 6 to 93; mean days between doses averaged 17.1 for patients who received standard edu-cational materials, compared with 14.5 days for patients who also received extra instruction from nurses.4 Overall, said Dr. Feldman, studies show that within 3 years, adherence rates for the TNF inhibitors etanercept (Enbrel), adalimumab, and infliximab (Remicade, Janssen) fall to approximately 50%.

One way to assess compliance among patients who self-inject biologics involves a tangential question, he said. “Ask them, ‘Are you keeping the extra syringes you’ve accumulated in your refrigerator?’ There shouldn’t be any extra syringes.”

Reasons for poor adherence to psoriasis treatments range from poor motivation (patients might not be particularly both-ered by their skin disease) to a mistrust of doctors, and fears—whether founded or unfounded—about drugs such as topical steroids, he said. Other reasons include secondary gains, as well as forgetfulness, side effects, and the perceived burden of treatment, he added.

In a recently published multinational study, disappointment with treatment was also found to affect adherence.5 Many study patients reported that they had to go through a burdensome process of trial and error before receiving more potent topical options. Some patients also expressed unrealistic expecta-tions about treatment; their doctors had not told them what to expect. To improve adherence, said Dr. Feldman, physicians must establish trust among their patients.

“Convincing patients that one cares about them can be as simple as sitting down, palpating their lesions, and passing a lighted magnifier over them,” even if the lesions are un-mistakably psoriasis when viewed from across the room. He also recommended asking open-ended questions about patients’

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experience with their disease and directing patients to support groups for help with psychosocial issues.

Furthermore, he said, optimizing treatment requires giving clear written instructions, choosing fast-acting agents, and scheduling follow-up appointments 1 week after the initial visit instead of the usual 4- to 8-week follow-up. One study of atopic dermatitis showed that the early follow-up appointment prompted a 77% adherence rate, compared with a 54% rate without such a visit.6

Finally, Dr. Feldman said, “Don’t scare patients and their families with side effects.”

Instead, he suggested turning side effects into opportuni-ties. For example, “I tell patients with scalp psoriasis that the medication may sting, but that means it’s working. And for male patients, one could say, ‘Most guys don’t have what it takes to use this treatment.’ Appealing to patients’ pride may work wonders.”

References1. Storm A, Andersen SE, Benfeldt E, Serup J. One in 3 prescriptions

are never redeemed: Primary nonadherence in an outpatient clinic. J Am Acad Dermatol 2008;59(1):27–33.

2. Tan X, Feldman SR, Chang J, Balkrishnan R. Topical drug delivery systems in dermatology: A review of patient adherence issues. Exp Opin Drug Deliv 2012;9(10):1263–1271.

3. Krejci-Manwaring J, Tusa MG, Carroll C, et al. Stealth moni-toring of adherence to topical medication: Adherence is very poor in children with atopic dermatitis. J Am Acad Dermatol 2007;56(2):211–216.

4. West C, Narahari S, O’Neill J, et al. Adherence to adalimumab in patients with moderate to severe psoriasis. Dermatol Online J 2013;19(5):18182.

5. Bewley A, Burrage DM, Ersser SJ, et al. Identifying individual psychosocial and adherence support needs in patients with pso-riasis: A multinational two-stage qualitative and quantitative study. J Eur Acad Dermatol Venereol, May 13, 2013 (online).

6. Sagransky MJ, Yentzer BA, Williams LL, et al. A randomized controlled pilot study of the effects of an extra office visit on adherence and outcomes in atopic dermatitis. Arch Dermatol 2010;146(12):1428–1430. n

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