Research Spotlight

Frieder, J., D. Kivelevitch, I. Haugh, I. Watson and A. Menter (2018). “Anti-IL-23 and Anti-IL-17 Biologic Agents for the Treatment of Immune-Mediated Inflammatory Conditions.” Clin Pharmacol Ther 103(1): 88-101.

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Advancements in the immunopathogenesis of psoriasis have identified interleukin (IL)-23 and IL-17 as fundamental contributors in the immune pathways of the disease. Leveraging these promising therapeutic targets has led to the emergence of a number of anti-IL-23 and -17 biologic agents with the potential to treat multiple conditions with common underlying pathology. The unprecedented clinical efficacy of these agents in the treatment of psoriasis has paved way for their evaluation in diseases such as psoriatic arthritis, Crohn’s disease, rheumatoid arthritis, in addition to other immune-mediated conditions. Here we review the IL-23/IL-17 immune pathways and discuss the key clinical and safety data of the anti-IL-23 and anti-IL-17 biologic agents in psoriasis and other immune-mediated diseases.

Frieder, J., D. Kivelevitch, C. T. Fiore, S. Saad and A. Menter (2018). “The impact of biologic agents on health-related quality of life outcomes in patients with psoriasis.” Expert Rev Clin Immunol 14(1): 1-19.

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INTRODUCTION: Psoriasis is a common, immune-mediated skin disease often associated with significant physical and psychosocial impairment. Antipsoriatic biologic agents offer patients unparalleled treatment potential in regard to greater skin clearance and overall improved quality of life. Evaluation of the therapeutic efficacy of biologic agents on the full psoriasis disease burden must account for their impact on both physical symptoms, as well as patient-reported, health-related quality of life (HRQoL) measurements. Areas covered: Results from numerous clinical trials demonstrate the significant clinical efficacy of biological agents targeting tumor necrosis factor-alpha (TNF-alpha) and the interleukin (IL)-12/23 and IL-17 immune pathways. However, relatively limited data is available evaluating their full effect on quality of life outcomes. This review will discuss the most relevant and up-to-date clinical data on HRQoL measurements related to treatment with these aforementioned biologic agents. Expert commentary: Patient-reported outcomes (i.e. Dermatology Life Quality Index) are being used with increasing frequency in clinical trials, and provide valuable information on the impact of psoriasis on numerous aspects of day-to-day living. These outcomes must also be incorporated in clinical practice, in addition to physical assessment of disease severity, treatment decisions, and therapeutic response in the psoriasis patient population.

Feldman, T. E., M. J. Reardon, V. Rajagopal, R. R. Makkar, T. K. Bajwa, N. S. Kleiman, A. Linke, D. J. Kereiakes, R. Waksman, V. H. Thourani, R. C. Stoler, G. J. Mishkel, D. G. Rizik, V. S. Iyer, T. G. Gleason, D. Tchetche, J. D. Rovin, M. Buchbinder, I. T. Meredith, M. Gotberg, H. Bjursten, C. Meduri, M. H. Salinger, D. J. Allocco and K. D. Dawkins (2018). “Effect of Mechanically Expanded vs Self-Expanding Transcatheter Aortic Valve Replacement on Mortality and Major Adverse Clinical Events in High-Risk Patients With Aortic Stenosis: The REPRISE III Randomized Clinical Trial.” Jama 319(1): 27-37.

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Importance: Transcatheter aortic valve replacement (TAVR) is established for selected patients with severe aortic stenosis. However, limitations such as suboptimal deployment, conduction disturbances, and paravalvular leak occur. Objective: To evaluate if a mechanically expanded valve (MEV) is noninferior to an approved self-expanding valve (SEV) in high-risk patients with aortic stenosis undergoing TAVR. Design, Setting, and Participants: The REPRISE III trial was conducted in 912 patients with high or extreme risk and severe, symptomatic aortic stenosis at 55 centers in North America, Europe, and Australia between September 22, 2014, and December 24, 2015, with final follow-up on March 8, 2017. Interventions: Participants were randomized in a 2:1 ratio to receive either an MEV (n = 607) or an SEV (n = 305). Main Outcomes and Measures: The primary safety end point was the 30-day composite of all-cause mortality, stroke, life-threatening or major bleeding, stage 2/3 acute kidney injury, and major vascular complications tested for noninferiority (margin, 10.5%). The primary effectiveness end point was the 1-year composite of all-cause mortality, disabling stroke, and moderate or greater paravalvular leak tested for noninferiority (margin, 9.5%). If noninferiority criteria were met, the secondary end point of 1-year moderate or greater paravalvular leak was tested for superiority in the full analysis data set. Results: Among 912 randomized patients (mean age, 82.8 [SD, 7.3] years; 463 [51%] women; predicted risk of mortality, 6.8%), 874 (96%) were evaluable at 1 year. The primary safety composite end point at 30 days occurred in 20.3% of MEV patients and 17.2% of SEV patients (difference, 3.1%; Farrington-Manning 97.5% CI, -infinity to 8.3%; P = .003 for noninferiority). At 1 year, the primary effectiveness composite end point occurred in 15.4% with the MEV and 25.5% with the SEV (difference, -10.1%; Farrington-Manning 97.5% CI, -infinity to -4.4%; P<.001 for noninferiority). The 1-year rates of moderate or severe paravalvular leak were 0.9% for the MEV and 6.8% for the SEV (difference, -6.1%; 95% CI, -9.6% to -2.6%; P < .001). The superiority analysis for primary effectiveness was statistically significant (difference, -10.2%; 95% CI, -16.3% to -4.0%; P < .001). The MEV had higher rates of new pacemaker implants (35.5% vs 19.6%; P < .001) and valve thrombosis (1.5% vs 0%) but lower rates of repeat procedures (0.2% vs 2.0%), valve-in-valve deployments (0% vs 3.7%), and valve malpositioning (0% vs 2.7%). Conclusions and Relevance: Among high-risk patients with aortic stenosis, use of the MEV compared with the SEV did not result in inferior outcomes for the primary safety end point or the primary effectiveness end point. These findings suggest that the MEV may be a useful addition for TAVR in high-risk patients.

Filardo, G., B. L. Hamman, B. da Graca, D. M. Sass, N. J. Machala, S. Ismail, B. D. Pollock, A. W. Collinsworth and P. A. Grayburn (2018). “Efficacy and effectiveness of on- versus off-pump coronary artery bypass grafting: A meta-analysis of mortality and survival.” J Thorac Cardiovasc Surg 155(1): 172-179.e175.

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BACKGROUND: Despite many studies comparing on- versus off-pump coronary artery bypass graft (CABG), there is no consensus as to whether one of these techniques offers patients better outcomes. METHODS: We searched PubMed from inception to June 30, 2015, and identified additional studies from bibliographies of meta-analyses and reviews. We identified 42 randomized controlled trials (RCTs) and 31 rigorously adjusted observational studies (controlling for the Society of Thoracic Surgeons-recognized risk factors for mortality) reporting mortality for off-pump versus on-pump CABG at specified time points. Trial data were extracted independently by 2 researchers using a standardized form. Differences in probability of mortality (DPM) were estimated for the RCTs and observational studies separately and combined, for time points ranging from 30 days to 10 years. RESULTS: RCT-only data showed no significant differences at any time point, whereas observational-only data and the combined analysis showed short-term mortality favored off-pump CABG (n = 1.2 million patients; 36 RCTs, 26 observational studies; DPM [95% confidence interval (CI)], -44.8% [-45.4%, -43.8%]) but that at 5 years it was associated with significantly greater mortality (n = 60,405 patients; 3 RCTs, 5 observational studies; DPM [95% CI], 10.0% [5.0%, 15.0%]). At 10 years, only observational data were available, and off-pump CABG showed significantly greater mortality (DPM [95% CI], 14.0% [11.0%, 17.0%]). CONCLUSIONS: Evidence from RCTs showed no differences between the techniques, whereas rigorously adjusted observational studies (with >1.1 million patients) and the combined analysis indicated that off-pump CABG offers lower short-term mortality but poorer long-term survival. These results suggest that, in real-world settings, greater operative safety with off-pump CABG comes at the expense of lasting survival gains.

Driver, S., M. Reynolds, M. Douglas and M. Bennett (2018). “Describing Weight Loss Attempts and Physical Activity Among Individuals With TBI Prior to Participation in a Weight-Loss Program.” J Head Trauma Rehabil 33(1): E36-e43.

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OBJECTIVE: Describe (1) weight loss history, (2) perceptions about lifestyle changes, and (3) physical activity among a sample of individuals with traumatic brain injury prior to a 12-month lifestyle change program. SETTING: Community-based. PARTICIPANTS: Individuals enrolled in a lifestyle change program, 6 months or more post-traumatic brain injury, body mass index of 25 or greater, 18 to 64 years of age, with physician’s clearance to participate. DESIGN: Convenience sample. MAIN MEASURES: Self-report data were collected before beginning the lifestyle change program including descriptive, weight loss history and physical activity behavior using the Modifiable Activity Questionnaire. RESULTS: The final sample included 22 participants (M age = 46 years) injured a median of 8 years ago. Mean weight was 208.5 lb (SD = 40.2), with average body mass index of 31.84 (SD = 4.4). Since injury, 72.7% reported prior weight loss attempts, with 50% gaining 10 lb or more. All participants indicated high motivation for lifestyle changes. Perceived benefits included feeling better, improving overall health, and increased energy. Barriers included physical health complications. Types of physical activity completed included walking (68%, 180 min/mo) and swimming (32%, 79 min/mo). CONCLUSION: Results indicate that many individuals gained weight since injury and attempted weight loss, demonstrating a need for evidence-based lifestyle interventions. Future research is needed to determine whether individuals with traumatic brain injury are able to achieve and maintain weigh loss through intervention.