Oral ponesimod is a new therapy for the treatment of moderate-to-severe plaque psoriasis. Vaclavkova et al conducted a phase 2 trial that demonstrated moderate efficacy of ponesimod in the treatment of psoriasis. Here we discuss various biologic agents with alternative mechanisms of action, that have demonstrated superior efficacy in psoriasis, and call into question the risks versus benefits of ponesimod therapy.

Psoriasis is a largely researched topic with abundant potential for publication in dermatologic journals. We used the Thomson Reuters’ Web of Science citation database using the search term “psoriasis” in the titles of any literature published in 4 high-impact dermatology journals. We compiled a ranking of the top 25 cited first authors and top 25 cited authors overall on the subject of psoriasis between 2000-2012. We hope our analysis highlights the achievements of our colleagues and predecessors

Background

The exponential growth of the biomedical literature necessitates investigating strategies to reduce systematic reviewer burden while maintaining the high standards of systematic review validity and comprehensiveness.

Methods

We compared the traditional systematic review screening process with (1) a review-of-reviews (ROR) screening approach and (2) a semi-automation screening approach using two publicly available tools (RobotAnalyst and AbstrackR) and different types of training sets (randomly selected citations subjected to dual-review at the title-abstract stage, highly curated citations dually reviewed at the full-text stage, and a combination of the two). We evaluated performance measures of sensitivity, specificity, missed citations, and workload burden RESULTS: The ROR approach for treatments of early-stage prostate cancer had a poor sensitivity (0.54) and studies missed by the ROR approach tended to be of head-to-head comparisons of active treatments, observational studies, and outcomes of physical harms and quality of life. Title and abstract screening incorporating semi-automation only resulted in a sensitivity of 100% at high levels of reviewer burden (review of 99% of citations). A highly curated, smaller-sized, training set (n = 125) performed similarly to a larger training set of random citations (n = 938).

Conclusion

Two approaches to rapidly update SRs-review-of-reviews and semi-automation-failed to demonstrate reduced workload burden while maintaining an acceptable level of sensitivity. We suggest careful evaluation of the ROR approach through comparison of inclusion criteria and targeted searches to fill evidence gaps as well as further research of semi-automation use, including more study of highly curated training sets.

Receptor clustering is the first and critical step to activate apoptosis by death receptor-5 (DR5). The recent discovery of the autoinhibitory DR5 ectodomain has challenged the long-standing view of its mechanistic activation by the natural ligand Apo2L. Because the autoinhibitory residues have remained unknown, here we characterize a crucial patch of positively charged residues (PPCR) in the highly variable domain of DR5. The PPCR electrostatically separates DR5 receptors to autoinhibit their clustering in the absence of ligand and antibody binding. Mutational substitution and antibody-mediated PPCR interference resulted in increased apoptotic cytotoxic function. A dually specific antibody that enables sustained tampering with PPCR function exceptionally enhanced DR5 clustering and apoptotic activation and distinctively improved the survival of animals bearing aggressive metastatic and recurrent tumors, whereas clinically tested DR5 antibodies without PPCR blockade function were largely ineffective. Our study provides mechanistic insights into DR5 activation and a therapeutic analytical design for potential clinical success.