Paul F. Lizzul

NF-κB: an essential transcription factor in psoriasis.

Nuclear factor kappa B (NF-κB) is a protein transcription factor that orchestrates inflammation and other complex biological processes. It is a key regulatory element in a variety of immune and inflammatory pathways, in cellular proliferation and differentiation and in apoptosis. Therefore NF-κB is a crucial mediator involved in the pathogenesis of psoriasis. Psoriasis, an inflammatory dermatosis, is marked by elevated levels of active, phosphorylated NF-κB. Genomic studies have also linked psoriasis with mediators in the NF-κB pathway. NF-κB has been hypothesized to connect the altered keratinocyte and immune cell behavior that characterizes the psoriatic milieu. Several anti-psoriatic therapies, including tumor necrosis factor-α blockers and glucocorticoids, reduce active NF-κB levels and related down-stream elements, and other biologics currently in development, including interleukin-17 blockers, may also target this pathway. Compounds that specifically target NF-κB signaling may be developed as novel therapeutics for chronic inflammatory disorders including psoriasis. However, chronic NF-κB inhibition could also result in immunodeficiencies. Therefore, a delicate balance must be found that maximizes therapeutic potential while limiting harmful effects, and may be achieved through several possible approaches, including localized therapy, selective inhibition of NF-κB signaling in pathologic cells, incomplete pathway inhibition or short treatment durations.

Investigator-initiated, open-label trial of ustekinumab for the treatment of moderate-to-severe palmoplantar psoriasis

Abstract Background: Palmoplantar psoriasis is a variant of psoriasis resistant to many forms of treatment. Methods: Twenty subjects with moderate-to-severe psoriasis of the palms and soles, 50% with pustules at baseline, were treated with ustekinumab at weeks 0, 4, and 16. All subjects had previously failed topical corticosteroids. Dosing was 45 mg subcutaneously for subjects weighing <100 kg and 90 mg for subjects weighing ≥100 kg. The primary endpoint was the percent of subjects achieving clinical clearance at week 16, defined as Palm–Sole Physicians Global Assessment ≤1. The study received Tufts Medical Center IRB approval. Results:After 16 weeks of treatment, 35% (7/20) of subjects achieved clinical clearance. Sixty percent (12/20) improved two or more points on the Palm–Sole Physicians Global Assessment scale. Sixty-seven percent (6/9) of those receiving the 90 mg ustekinumab dose achieved clinical clearance compared with nine percent (1/11) receiving 45 mg (p = 0.02). At 24 weeks, mean values showed 56% improvement in Dermatology Life Quality Index, and 34% improvement in pain Visual Analogue Scale score (all p < 0.05). Limitations: Assessment tools for palmoplantar psoriasis are not yet validated. Five subjects withdrew or were lost to follow-up. Conclusion: This study demonstrates that ustekinumab dosed at 90 mg is effective in controlling signs and symptoms of palmoplantar psoriasis.

Management of psoriatic arthritis from the view of the dermatologist

Psoriatic arthritis (PsA) is an inflammatory seronegative spondyloarthropathy associated with psoriasis. Although the main assessment measures for PsA are borrowed from the standard criteria used to assess rheumatoid arthritis, a number of new criteria such as the PsAJAI and CPDAI are being developed specifically for PsA. Long-term consequences of untreated PsA include persistent inflammation, progressive joint damage and, in many cases, substantial functional limitations, pain and disability. Moreover, patients with PsA have an increased mortality risk and an increased risk of developing cardiovascular disease and metabolic syndrome. Both GRAPPA and the AAD have developed treatment guidelines, which are discussed here. Psoriasis commonly precedes arthritic symptoms; thus, dermatologists are ideally placed to make the initial diagnosis of PsA and treat it appropriately, affording the opportunity to slow disease progression, improve physical function and enhance quality of life. This Review explores the management of patients with PsA, with a particular emphasis on assessment tools, long-term consequences and treatment issues from the viewpoint of the dermatologist.

Prevalence of the Metabolic Syndrome in Children with Psoriatic Disease

Adults with psoriasis have a greater risk of developing metabolic syndrome (MetS) and cardiovascular disease (CVD), but few studies have investigated the prevalence of MetS and other risk factors for CVD in children with psoriasis. In an assessor‐blinded study, 20 children ages 9–17 years with a current or previously documented history of psoriasis involving 5% or more of their body surface area or psoriatic arthritis were compared with a cohort of age‐ and sex‐matched controls with benign nevi, warts, or acne. MetS, our primary endpoint, was defined by the presence of abnormal values in at least three of the following measures: triglycerides, high‐density lipoprotein cholesterol (HDL‐C), fasting blood glucose (FBG), waist circumference, and blood pressure. Secondary endpoints included high‐sensitivity C‐reactive protein (hs‐CRP), total cholesterol (TC), and low‐density lipoprotein cholesterol (LDL‐C). Thirty percent (6/20) of children with psoriasis met the criteria for MetS, compared with 5% (1/20) of the control group (p < 0.05). Subjects with psoriasis had higher mean FBG (91.1 mg/dL) than the control group (82.9 mg/dL) (p = 0.01). There were no statistically significant differences in the other four components of MetS, BMI, BMI percentile, hs‐CRP, TC, or LDL‐C. The results of this trial demonstrate that children with psoriasis have higher rates of MetS than age‐ and sex‐matched controls. It may therefore be important to evaluate children with psoriasis for components of MetS to prevent future CVD morbidity and mortality.

Physician performance measurement: tiered networks and dermatology (an opportunity and a challenge).

INTRODUCTION Over the past few years, the emergence of public profiling of physicians by health plans, pay-forperformance (P4P) contracts, and tiered provider networks have been heralded as endeavors to improve the delivery of medical care. Designed to align financial incentives and outcomes and rein in healthcare costs while demanding a purported higher quality of care, these efforts have been met with skepticism, confusion, and, at times, hostility from physicians. The medical profession, in principle, understands and supports efforts by insurance carriers to achieve more efficient and effective care. However, the execution of these programs has been concerning to the dermatology community in particular, given the challenges associated with identifying quality within this specialty in the ambulatory care setting and subsequently measuring it appropriately. As healthcare reform efforts infiltrate specialty markets, it is critical that all stakeholders understand and are prepared for the changes that will impact the way patient care is promoted, paid for, and measured. Herein we discuss ratings of physicians as they apply to the practice of dermatology and how they are used to create tiered networks. In addition, we share how tiered networks, if not implemented correctly, may undermine the improvements they seek. Finally, we suggest strategies for both payers and providers that will support transparency,

Overview of ATX-101 (Deoxycholic Acid Injection): A Nonsurgical Approach for Reduction of Submental Fat.

Abstract In 2015, ATX-101 (deoxycholic acid injection; Kybella in the United States and Belkyra in Canada; Kythera Biopharmaceuticals, Inc., Westlake Village, CA [an affiliate of Allergan plc, Dublin, Ireland]) was approved as a first-in-class injectable drug for improvement in the appearance of moderate to severe convexity or fullness associated with submental fat. ATX-101 has been evaluated in a clinical development program that included 18 Phase 1 to 3 studies supporting the current indication. Since 2007, the toxicity and safety profiles of ATX-101 have been characterized in numerous preclinical studies, its pharmacokinetics, pharmacodynamics, and optimal treatment paradigm have been defined in multiple Phase 1 and 2 studies, and its efficacy and clinical safety have been confirmed in 4 large Phase 3 trials (2 conducted in Europe and 2 in the United States and Canada [REFINE-1 and REFINE-2]). As subcutaneous injection of deoxycholic acid has been shown to cause adipocytolysis, the reduction in submental fat achieved after ATX-101 treatment is expected to be long lasting. This prediction is confirmed by data from long-term follow-up studies of up to 4 years after last treatment with ATX-101, which demonstrate that the treatment response is maintained over time in most subjects. ATX-101 offers a durable, minimally invasive alternative to liposuction and surgery for addressing submental fullness.

Efficacy and Safety of ATX-101 by Treatment Session: Pooled Analysis of Data From the Phase 3 REFINE Trials

Abstract Background ATX-101 (deoxycholic acid injection) is the only injectable drug approved for submental fat (SMF) reduction. In the phase 3 REFINE trials, adults with moderate or severe SMF who were dissatisfied with the appearance of their face/chin were eligible to receive up to 6 treatment sessions with ATX-101 (2 mg/cm2) or placebo. Primary and secondary endpoints, evaluated at 12 weeks after last treatment, significantly favored ATX-101 supporting its efficacy for reducing SMF and the psychological impact of SMF, and increasing satisfaction with the appearance of the face/chin. Objectives To evaluate the efficacy and safety of ATX-101 by treatment session. Methods This post hoc analysis used pooled data from the REFINE trials to evaluate efficacy endpoints and adverse events following each treatment session to further characterize the ATX-101 treatment response and safety profile. Results In both treatment groups, mean injection volume declined over subsequent treatment sessions, though more markedly in the ATX-101 group. The majority of ATX-101–treated patients achieved a ≥1-grade improvement in SMF within 2 to 4 treatment sessions based on either clinician or patient assessment. Furthermore, 19.1% of ATX-101–treated patients (vs 3.9% of placebo-treated patients) received fewer than 6 treatment sessions owing to patient satisfaction with treatment or lack of sufficient SMF for further treatment. In both treatment groups, the incidence/severity of common injection-site adverse events declined over subsequent treatment sessions. Conclusions Although up to 6 treatment sessions were permitted in the REFINE trials, most ATX-101–treated patients achieved an improvement in SMF within 2 to 4 treatment sessions. Level of Evidence: 3

Impact of Accountable Care Organizations on Psoriasis Care

The Center for Medicare and Medicaid Services implemented the groundwork for health care providers to use integrated delivery models, such as accountable care organizations, which are designed to improve quality of care while decreasing costs. The objective of these units is to promote health maintenance through primary care services and to avoid inpatient hospitalizations. This strategy may not account for the role of specialty services, like dermatology, that are primarily conducted in an outpatient setting. Psoriatic patients, who are regularly seen in dermatology clinics, represent a model patient cohort with a chronic, complex, and debilitating skin disorder that incurs significant annual costs. Accountable care organizations can hinder appropriate referrals for these at-risk patients, leading to greater morbidity and possibly even greater costs. While rising health care costs make reforms necessary, it is crucial that the impact of accountable care organizations across all facets of healthcare be examined to be effective.