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

Psoriasis and Psoriatic Arthritis Treatment

Alan Menter, MD
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.
      The development of biologic therapies targeting key molecules involved in disease pathogenesis has revolutionized the treatment of moderate to severe psoriasis and PsA.15 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

TNF Inhibitors
      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.15 Therapies targeting TNF reduce the signs and symptoms of joint disease in the majority of patients with PsA.15 TNF inhibitors are also effective at addressing extra-articular manifestations of PsA, including skin involvement, axial disease, enthesitis, and dactylitis.11 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.27

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.28 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
follow-up.29 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.28,29
     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.15 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.30,31 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.32
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).33 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.34

IL-17 Inhibitors
     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.15

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
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.37-39 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).37 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
infection relative to placebo.37-39

     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.41

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.41-43 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.42
     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.44

     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.45 Brodalumab has been shown to significantly improve the clinical signs and symptoms of psoriasis and PsA.46-48 However, the clinical development of brodalumab has been complicated by safety concerns, particularly rare reports of suicidal ideation in these patient populations.49 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, 2016.50

Small-Molecule Inhibitors 
      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.12

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