Noori Kim

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.

Phosphodiesterase 4-targeted treatments for autoimmune diseases

Advancements in phosphodiesterase (PDE)-targeted therapies have shown promise in recent years for treating patients with a variety of autoimmune diseases. This review summarizes the development of PDE4 inhibitors and the associated literature with a focus on treatments for autoimmune diseases. After the initial investigations of the prototypic PDE inhibitor, rolipram, more selective inhibitors targeting the PDE4 isozyme have been developed. With phase II and phase III clinical trials currently underway to evaluate the safety and efficacy of the latest generation of PDE4 inhibitors, namely apremilast, a new class of treatments may be around the corner for patients suffering from chronic, autoimmune diseases.

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.

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.

Diagnosing and treating psoriatic arthritis: An update

Psoriatic arthritis (PsA) is an inflammatory arthritis of uncertain pathogenesis, affecting approximately one in four patients with psoriasis. Onset of psoriasis typically precedes the development of PsA. Therefore, the dermatologist is ideally positioned to recognize the early signs and symptoms of PsA for diagnosis and subsequent treatment. The role of the dermatologist in early diagnosis and treatment is essential for preventing pain and functional disabilities, as well as the joint deterioration that accompanies progressive forms of PsA. Diagnosis of PsA is a key aspect of the clinical decision process for the dermatologist, as psoriasis plus PsA requires a different therapeutic approach from that required for psoriasis alone. Furthermore, PsA is associated with an increased risk of cardiovascular comorbidities that present significant health concerns. In this review, the pathogenesis and comorbidities of PsA are discussed. In addition, screening and imaging tools that aid in the diagnosis of PsA, as well as tools used for efficacy assessment, are reviewed. Available therapies are presented, with a focus on targeted biologics and emerging treatments.

Patch test results in psoriasis patients on biologics.

ObjectivesThe objective of this study was to determine the prevalence of positive patch tests in patients with psoriasis receiving biologics and whether these results differ from those of patients with psoriasis not on biologics. MethodsAn institutional review board–approved retrospective chart review was conducted for patients with psoriasis patch tested January 2002–2012 at Tufts Medical Center. Patients had a history of psoriasis, psoriatic arthritis, and patch testing as identified by International Classification of Diseases, Ninth Revision codes 696.1, 696.0, and 95044, respectively, in their records. Patients were tested to a modified North American Contact Dermatitis Group standard and cosmetics series. Readings were performed at 48 hours and 72 to 96 hours. The North American Contact Dermatitis Group grading system was used to grade reactions. ResultsFifteen patients with psoriasis on biologics (cases) and 16 patients with psoriasis not on biologics (control subjects) were studied. The biologics used were ustekinumab (n = 7), etanercept (n = 4), adalimumab (n = 3), and infliximab (n = 1). Eighty percent (12/15) of cases had at least 1 positive reaction compared with 81% (13/16) of the control subjects; 67% (10/15) of cases had 2+ reactions compared with 63% (10/16) of the control subjects, and 27% (4/15) of cases had 3+ reactions, compared with 38% (6/16) of control subjects. These differences were not statistically significant. ConclusionsGiven the limitation of small numbers of patients, biologics do not appear to influence the abilities of patients with psoriasis to mount a positive patch test.

Outcome Measures in Psoriasis and Psoriatic Arthritis

The recent health policy imperatives in the United States have consequentially called to attention the absence of dermatologic evaluations in the health outcome and quality measures that will ultimately grade the success of providers. Psoriasis, in particular, represents a patient cohort with a chronic, complex and debilitating skin disorder commonly encountered in dermatology clinics that can have insufferable consequences from disease progression and comorbidities if it is not properly evaluated and managed. In order to have the appropriate compensation to the providers and the availabilities of the correct treatments to the patients, the presence of psoriasis-specific outcome measures are necessary. Incorporating the concepts employed by the rheumatology group, Outcome Measures for Rheumatoid Arthritis Clinical Trials (OMERACT), that created outcomes for several musculoskeletal diseases, initiatives in dermatology have already begun to create standardized, validated psoriasis outcome measures.

Psoriasis: Ustekinumab and Other Biologics in the Pipeline

The improved understanding of the complex immunology and pathogenesis of psoriasis and psoriatic arthritis has established the therapeutic utility of targeted biologic therapies against the pathogenic T cells and the inflammatory cytokines. Particular interest in the interleukin (IL)-23/T helper (Th)17 pathway has led to the development of ustekinumab, which is now approved and widely marketed for the treatment of psoriasis, as well as various investigational biologic agents in current clinical trials. Lack of or improper treatment of psoriasis and psoriatic arthritis can inevitably result in considerable morbidity and quality of life issues for affected patients, emphasizing the continued need for drug research and development to achieve optimal management.

IDEOM: International Dermatology Outcome Measures – Proceedings from the First Meeting

SUMMER 2014 Varada et al. | PSORIASIS FORU M, VOL. 20, NO. 2 Sowmya Varada, B.S., Tufts Medical Center; Noori Kim, M.D., Tufts Medical Center; April Abernethy, N.D., National Psoriasis Foundation; April Armstrong, M.D., M.P.H., University of California Davis; Kristina Callis-Duffin, M.D., University of Utah; Amit Garg, M.D., Boston University; Alice Gottlieb, M.D., Ph.D., Tufts Medical Center IDEOM: International Dermatology Outcome Measures – Proceedings from the First Meeting

Psoriatic Arthritis: Clinical Review and Update

Psoriatic arthritis (PsA) a debilitating, seronegative spondyloarthropathy associated with psoriasis. The prevalence of PsA among psoriatic patients is estimated to be between 7 and 42 %. Skin lesions of psoriasis most often precede arthritic symptoms, however up to 20 % of patients with PsA manifest joint disease prior to skin involvement. Potential benefits of treatment include better quality of life and radiologic improvement of joint damage. Currently no universally accepted gold standard exists for diagnosing PsA, although the ClASsification criteria for Psoriatic Arthritis (CASPAR) criteria may gain widespread acceptance. While there is no universal agreement on the most accurate methods to evaluate PsA treatment, the Outcome Measures in Rheumatology (OMERACT) and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) recommend using tools to assess of joint, skin, function, pain, patient’s global assessment and quality of life. Treatment guidelines vary between GRAPPA and AAD, but generally recommend that mild PsA should be managed with NSAIDs and intralesional corticosteroid injections, and moderate to severe PsA should be managed with methotrexate or biologics. Biologic therapies, including TNF-α inhibitors, are recommended in the treatment of moderate to severe PsA, especially those patients with poor prognostic factors. With the potential benefits of early treatment, dermatologists and rheumatologists are strongly encouraged to assess patients for the signs and symptoms of PsA at each visit.