New Focus for Inflammatory Skin Disease and Psoriasis: Topical Glucose Transport Inhibitors

MedicalResearch.com Interview with:

Richard Wang, M.D., Ph.D.  Assistant Professor Dermatology UT Southwestern Medical Center 

Richard Wang, M.D., Ph.D. 
Assistant Professor Dermatology
UT Southwestern Medical Center 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Targeting cellular metabolism is currently being explored as a new way to diagnose and treat diseases. In particular, there has been increasing interest in specifically targeting metabolic pathways are preferentially altered in disease states, like cancer.  Although an increased dependence on glucose transport and metabolism has been well established for rapidly proliferating cells, attempts to target this conserved pathway have been limited by concerns about the high potential for side effects from the systemic inhibition of glucose transport.

To investigate the feasibility of targeting glucose transport in skin diseases, we investigated the effect of inhibiting glucose transport in the skin by deleting the primary glucose transporter in the skin, Glut1, in mouse keratinocytes. We confirmed that the Glut1-deficient keratinocytes showed metabolic and oxidative stress and impaired proliferation. However, the keratinocyte-specific ablation of Glut1 did not compromise mouse skin development and barrier function. Metabolomic profiling revealed sphingolipid, hexose, amino acid, and nucleotide adaptations in Glut1-deficient keratinocytes. However, Glut1 deficient skin did show defects in both proliferation and migration after physiologically relevant stressors like excisional wounds and UV-B irradiation.

Given its importance during stressors, we further tested whether Glut1 was important in the pathogenesis of psoriasis models. Notably, both the genetic and pharmacological inhibition of Glut1 decreased hyperplasia in mouse and human organic models of psoriasis. Moreover, the topical application of a Glut1 inhibitor further decreased inflammation in these models. The ability to deliver glucose transport inhibitors specifically to the skin may limit the adverse effects from the systemic inhibition of glucose transport and suggests that the topical inhibition of glucose transport may be a novel approach to treat hyperproliferative and inflammatory skin diseases.  Continue reading

Ixekizumab Improved Impact of Genital Psoriasis on Sexual Activity

MedicalResearch.com Interview with:

Dr. Jennifer Cather MD Medical Director at Modern Dermatology and Modern Research Associate Dallas, Texas 

Dr. Cather

Dr. Jennifer Cather MD
Medical Director at Modern Dermatology and Modern Research Associate
Dallas, Texas 

MedicalResearch.com: What is the background for this study? What are the main findings? 

Response: Genital psoriasis can be an uncomfortable and burdensome condition that many people living with moderate-to-severe plaque psoriasis experience. Due to the significant impact, Lilly conducted a 12-week Phase 3b clinical trial with patients with moderate-to-severe genital psoriasis treated with ixekizumab, which found that patients had a greater decrease in the impact of their condition on sexual activity compared to placebo as early as one week.

Specifically, trial patients were randomized to receive ixekizumab (80 mg every two weeks, following a 160-mg starting dose) or placebo and researchers measured pre-specified patient-reported outcomes, including the Genital Psoriasis Sexual Impact Scale (GPSIS), which is composed of the Sexual Activity Avoidance (Avoidance) and Impact of Sexual Activity on Genital Psoriasis Symptoms (Impact) subscales. Patient-reported outcomes were also measured by the Sexual Frequency Questionnaire (SFQ) item 2, evaluating the impact of genital psoriasis on the frequency of sexual activity, and the Dermatology Life Quality Index (DLQI) item 9, evaluating the impact of skin symptoms on sexual difficulties.

At 12 weeks, patients reported the following outcomes:

  • DLQI Item 9 0/1: 92.0 percent of patients treated with ixekizumab compared to 56.8 percent of patients treated with placebo reported no (0) or little (1) sexual difficulties caused by skin symptoms.
  • SFQ Item 2 0/1:  78.4 percent of patients treated with ixekizumab compared to 21.4 percent of patients treated with placebo (reported the frequency of sexual activity was either never (0) or rarely (1) limited by genital psoriasis.
  • GPSIS-Avoidance 1/2:  76.7 percent of patients treated with ixekizumab compared to 25.7 percent of patients treated with placebo reported never (1) or rarely (2) avoiding sexual activity due to genital psoriasis.
  • GPSIS-Impact 1/2:  85.7 percent of patients treated with ixekizumab compared to 52.9 percent of patients treated with placebo reported worsening of genital psoriasis symptoms during or after sexual activity was very low/none at all (1) or low (2). 

Continue reading

Treatment With Tremfya® (Guselkumab) Improved Psoriatic Arthritis Symptoms Through One Year

MedicalResearch.com Interview with:

Atul A. Deodhar, MD, MRCP, FACP, FACR Professor of Medicine Division of Arthritis & Rheumatic Diseases Medical Director, Rheumatology Clinics Medical Director, Immunology Infusion Center Oregon Health & Science University (OHSU) 

Dr. Deodhar

Atul A. Deodhar, MD, MRCP, FACP, FACR
Professor of Medicine
Division of Arthritis & Rheumatic Diseases
Medical Director, Rheumatology Clinics
Medical Director, Immunology Infusion Center
Oregon Health & Science University (OHSU) 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The Phase 2, randomized, double-blind, placebo–controlled, multicenter trial was designed to evaluate the efficacy and safety of guselkumab (Tremfya®) compared with placebo in adults with active psoriatic arthritis, despite having received treatment with standard-of-care therapies, including anti-tumor necrosis factor (TNF)-alpha agents.

In an observed analysis presented at ACR 2017, more than 70 percent of patients receiving guselkumab achieved at least a 20 percent improvement in signs and symptoms of disease (ACR 20) at week 56.  Findings also showed that improvements in tender and swollen joints, skin clearance, pain and physical function, and patient-reported quality of life outcomes reported at week 24, were maintained through week 56 in patients receiving guselkumab maintenance therapy (subcutaneous injections every eight weeks).  Continue reading

Severe Psoriasis Linked To Increased Risk of Mortality

MedicalResearch.com Interview with:

Megan H. Noe MD, MPH Clinical Instructor and Post-Doctoral Research Fellow University of Pennsylvania, Department of Dermatology Perelman Center for Advanced Medicine Philadelphia, PA 19104

Dr. Megan Noe

Megan H. Noe MD, MPH
Clinical Instructor and Post-Doctoral Research Fellow
University of Pennsylvania, Department of Dermatology
Perelman Center for Advanced Medicine
Philadelphia, PA 19104

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Previous research has shown that patients with psoriasis have higher rates of hypertension, diabetes, cardiovascular disease and chronic kidney disease that may put them at an increased risk of death.

Our research found that patients with psoriasis covering more than 10% of their body had almost double the risk of death than people of the same age with similar medical conditions, but without psoriasis.

Continue reading

Cardiovascular Events Rise With Increased Duration of Psoriasis

MedicalResearch.com Interview with:

Alexander Egeberg, MD PhD Gentofte Hospital Department of Dermatology and Allergy Kildegårdsvej 28 2900 Hellerup Denmark 

Dr. Egeberg

Alexander Egeberg, MD PhD
Gentofte Hospital
Department of Dermatology and Allergy
Kildegårdsvej 28
2900 Hellerup
Denmark

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The majority cardiovascular events in psoriasis occur in patients at low risk by traditional cardiovascular risk calculators. It has been speculated that long-term exposure to systemic inflammation may increase the risk of adverse cardiovascular outcomes. Therefore, clinically available historical features such as disease duration may identify those at higher risk for cardiovascular disease.

Using a translational epidemiological approach, combining 18F-fluorodeoxyglucose positron emission tomography computed tomography scanning with nationwide epidemiological data of more than four million individuals, we provide the first convincing evidence to suggest a detrimental effect of psoriasis duration on cardiovascular disease beyond traditional cardiovascular risk factors, even in patients deemed “low-risk” by conventional risk scores. We found a 1% increase in future major adverse cardiovascular event risk per additional year of disease duration. This finding has an effect size similar to smoking, a well-established cardiovascular risk factor.

Continue reading

Secukinumab Provides Sustained Improvements in Dermatology-Specific Quality of Life in Moderate to Severe Psoriasis Patients Through 3 Years of Treatment

MedicalResearch.com
Eric Hughes
Global Development Franchise Head Immunology & Dermatology
Novartis

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Psoriasis is a chronic immune-mediated inflammatory disease that negatively impacts patients’ quality of life (QOL); therefore QOL outcomes are increasingly recognized as an important measure of efficacy in psoriasis, complementing traditional measures of severity such as the Psoriasis Area and Severity Index (PASI).

Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin-17A (IL-17A), exhibits significant efficacy in the treatment of moderate-to-severe psoriasis, ankylosing spondylitis and psoriatic arthritis, demonstrating a rapid onset of action and a favorable safety profile.

Biologic therapies for psoriasis have previously been associated with a fall-off in efficacy over time; accordingly, extended follow-up is required to adequately evaluate novel therapeutic strategies like IL-17A inhibition. Recently, results from the extension of the SCULPTURE secukinumab trial showed that high responses initially achieved with secukinumab at year 1 in the SCULPTURE study were sustained over time up to 3 years with no new or unexpected safety concerns. In this analysis, we examined whether the sustained efficacy observed in SCULPTURE up to 3 years was translated into sustained effect of secukinumab on patient’s QOL measured by the Dermatology Life Quality Index (DLQI) questionnaire.

SCULPTURE, a multi-center extension study, was conducted with subjects who completed 52 weeks of treatment. Subjects were randomized into two maintenance dosing regimens; a fixed-interval schedule of secukinumab 300 mg every 4 weeks (Fixed interval dosing regimen (FI) cohort), and secukinumab retreatment-as-needed (Retreatment as needed (RAN) cohort), in which subjects received placebo until start of relapse, at which time secukinumab 300 mg every 4 weeks was re-initiated.

The analysis using as-observed data showed that at Year 3, improvements in the total score on DLQI was well sustained in both FI and RAN cohorts. Approximately two-thirds of the subjects in the FI cohort reported no impact of skin disease on QOL (corresponding to a score of 0 or 1 on DLQI). The proportion of patients in the RAN cohort reporting no impact of the disease on their QOL was well sustained through 3 years but remained consistently lower than those observed in the FI cohort. The results for each subscale of the DLQI questionnaire were consistent with those with DLQI total score i.e. showing high and sustained proportions of patients reporting no impact of the disease on different domains of health-related QOL in the two secukinumab cohorts with greater effect in the FI cohort compared to the RAN cohort.

Continue reading

Secukinumab (Cosentyx) Provides Greater Improvement in Quality of Life, Work Productivity, and Daily Activity Than Ustekinumab (Stelara) in Moderate To Severe Psoriasis

MedicalResearch.com Interview with:
Eric Hughes, Global Head of Development, Immunology & Dermatology

Novartis Pharma AG
Basel, Switzerland

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: It is well established that psoriasis negatively affects quality of life and work productivity. However, how the treatments affect psoriasis severity (based on skin clearance, itch, pain and scaling symptoms), health-related quality of life (HRQOL), work productivity, and daily activity directly or indirectly (via other factors) are still largely unknown.

Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin-17A (IL-17A), exhibits significant efficacy in the treatment of moderate-to-severe psoriasis, ankylosing spondylitis, and psoriatic arthritis, demonstrating a rapid onset of action and a favorable safety profile.

In CLEAR, a Phase 3b head-to-head study versus ustekinumab, secukinumab demonstrated sustained superior efficacy in clearing skin through Week 52, greater improvement in symptoms and HRQOL, greater relief of work and activity limitations, and a comparable safety profile. In this sub-analysis of the CLEAR study, Novartis was interested in examining the relationships among multiple variables that are thought to be important to patients with psoriasis. The direct and indirect (i.e. mediated) effects of treatment (secukinumab or ustekinumab) on psoriasis severity and patients’ HRQOL, work productivity, and daily activity were examined. The evaluation was conducted using structural equation modeling (or path analysis) and compared these relationships for secukinumab versus ustekinumab at 16 and 52 weeks. Structural equation modeling or path analysis is a statistical method that models the direct and indirect relationship between multiple patient-relevant outcomes simultaneously.

Goodness-of-fit statistics for all models were excellent confirming the robustness of the results. Results at Week 16 and at Week 52 for different Psoriasis Area and Severity Index (PASI) response categories (e.g. PASI 75, PASI 90, PASI 100) indicated that psoriasis treatment indirectly affected HRQOL and work productivity and daily activity, measured with the Dermatology Life Quality Index (DLQI) and the Work Productivity and Activity Impairment (WPAI) questionnaires, respectively.

Actually, greater effect of secukinumab over ustekinumab on DLQI was mediated by greater improvement of secukinumab in PASI response as well as by greater improvement in psoriasis-related symptoms (itch, pain and scaling). Greater effect of secukinumab over ustekinumab on work productivity and daily activity was mediated by greater improvement of secukinumab in psoriasis-related symptoms.

Continue reading

Psoriasis Patients At Higher Risk for Multiple Pathological Fractures

MedicalResearch.com Interview with:
Dr. Jonathan L. Silverberg MD PhD MPH

Assistant Professor in Dermatology
Medical Social Sciences and Preventive Medicine
Northwestern University, Chicago, Illinois

Dr. Jonathan L. Silverberg MD PhD MPH Assistant Professor in Dermatology Medical Social Sciences and Preventive Medicine Northwestern University, Chicago, Illinois

Dr. Jonathan Silverberg

Response: Psoriasis is associated with a number of potential risk factors for developing osteoporosis and pathological fractures, including including low vitamin D, chronic inflammation, higher rates of cigarette smoking and systemic corticosteroid usage. We hypothesized that adults with psoriasis have higher rates of osteoporosis and pathological fractures.

We examined data from the 2002-2012 National Inpatient Sample, which contains a representative 20% sample of all hospitalizations in the United States. We found that psoriasis was associated with higher odds of osteopenia, osteoporosis, osteomalacia, ankylosing spondylitis, and pathological fractures. In particular, psoriasis was associated with vertebral, pelvic, femoral and tibial/fibular fractures. The associations between psoriasis and pathological fractures were more pronounced in women than men.

Continue reading

Psoriasis: Efficacy and Safety of Guselkumab vs Humira for Moderate to Severe Disease

MedicalResearch.com Interview with:

Andrew Blauvelt, M.D., M.B.A. President and Investigator Oregon Medical Research Center

Dr. Blauvelt

Andrew Blauvelt, M.D., M.B.A.
President and Investigator
Oregon Medical Research Center

 MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Findings from the Phase 3 VOYAGE 1 study showed that patients with moderate to severe plaque psoriasis receiving guselkumab, an human anti-interleukin (IL)-23 monoclonal antibody, achieved significant improvement in skin clearance and in comparison with Humira® (adalimumab), a TNF blocker.  The Phase 3 study and head-to-head analysis of guselkumab vs. adalimumab showed the significant and durable efficacy of guselkumab as maintained through one year when compared with adalimumab, and the robust efficacy of this novel IL-23 targeted therapy in meeting all primary and major secondary endpoints.

Continue reading

Musculoskeletal Symptoms May Mark Onset of Arthritis in Psoriasis Patients

MedicalResearch.com Interview with:

Lihi Eder MD PhD Rheumatologist, Women’s College Hospital Scientist, Women’s College Research Institute Assistant Professor of Medicine, University of Toronto Toronto, ON, Canada

Dr. Lihi Eder

Lihi Eder MD PhD
Rheumatologist, Women’s College Hospital
Scientist, Women’s College Research Institute
Assistant Professor of Medicine, University of Toronto
Toronto, ON, Canada

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: There significant delays in the diagnosis of psoriatic arthritis (PsA) among patients with psoriasis. Many patients with psoriasis experience musculoskeletal symptoms. The majority of them do not have PsA, but other non-inflammatory conditions such as fibromyalgia or osteoarthritis.

In this study, we aimed to assess whether the presence and the degree of musculoskeletal symptoms in psoriasis patients predict the development of psoriatic arthritis. We analyzed a cohort of 410 psoriasis patients who were followed over a period of 9 years. These patients did not have arthritis at baseline. The patients were assessed annually by a rheumatologist for signs of PsA. A total of 57 patients developed psoriatic arthritis during the follow-up period.
Continue reading