The 2018 pipeline of targeted therapies under clinical development for Systemic Lupus Erythematosus: a systematic review of trials

Currently, Systemic Lupus Erythematosus (SLE) therapies range from antimalarials to glucocorticoids, in addition to immunosupressive agents or biologics such as rituximab or belimumab, when needed. Several unmet needs remain in the treatment SLE and more targeted drugs with improved safety profiles are expected. Based on recent advances in the understanding of the complex pathogenesis of SLE, several targeted treatments are currently assessed in clinical trials. In this study, we performed a systematic review of all targeted therapies under clinical development in SLE in 17 online registries of clinical trials. The search yielded a total of 1140 trials, from which we identified 74 targeted therapies for SLE. Those treatments target inflammatory cytokines, chemokines, or their receptors (n?=?17), B cells or plasma cells (n?=?17), intracellular signalling pathways (n?=?10), T/B cells costimulation molecules (n?=?8), interferons (n?=?7), plasmacytoid dendritic cells (pDC) (n?=?3), as well as various other targets (n?=?12). Not all these candidate drugs will reach phase III, but the broad spectrum of drugs being investigated may satisfy the urgent need for improved lupus medications. The identification of biomarkers that would allow adequate prediction of response-to-therapy remains high, but when solved will allow a more rationale selection of the optimal pharmacological agent at the patient level.     

Nuclear-specific AR-V7 Protein Localization is Necessary to Guide Treatment Selection in Metastatic Castration-resistant Prostate Cancer

Background

Circulating tumor cells (CTCs) expressing AR-V7 protein localized to the nucleus (nuclear-specific) identify metastatic castration-resistant prostate cancer (mCRPC) patients with improved overall survival (OS) on taxane therapy relative to the androgen receptor signaling inhibitors (ARSi) abiraterone acetate, enzalutamide, and apalutamide.

A randomized, double-blind, placebo-controlled study of verapamil and metoprolol in treatment of multifocal atrial tachycardia

PURPOSE: Multifocal atrial tachycardia is a difficult arrhythmia to treat. Patients not showing a response to the correction of predisposing conditions present a therapeutic dilemma. To assess the efficacy of two agents reported to be effective in this condition, verapamil, metoprolol, or placebo was given intravenously in a randomized, double-blind trial. PATIENTS AND METHODS: Thirteen patients meeting inclusionary criteria were enrolled. Therapeutic response was defined as conversion to sinus rhythm, a decline in the ventricular rate of 15 percent or more [corrected], or a ventricular rate of less than 100 beats/minute. Four male and nine female patients having a mean age (+/- SD) of 81.9 +/- 14.2 years were enrolled. Automated serum chemistries, complete blood cell count with differential, arterial blood gas values, and serum digoxin and theophylline levels were determined and a 12-lead electrocardiogram was obtained at the start of the trial. Following the completion of each phase of the study, a repeat physical examination was performed, and arterial blood gas values and an electrocardiogram were obtained. The trial was designed to run for two days. RESULTS: Two of 10 (20 percent), four of nine (44 percent), and eight of nine (89 percent) showed a response to placebo, verapamil, or metoprolol, respectively. Mean slowing of ventricular rate was 3.4, 7.3, and 24.5 percent for placebo, verapamil, and metoprolol, respectively (p less than 0.01 for metoprolol versus placebo). Five patients who showed a response to metoprolol had failed to have a response to verapamil. CONCLUSION: We conclude that metoprolol appears to be more effective than verapamil in treating multifocal atrial tachycardia. However, careful patient selection is necessary in its use.     

The Root-Ely Modified Test of Rectus Femoris Spasticity Has Reliability in Individuals with Cerebral Palsy

Background

Stiff-knee gait is a common gait deviation in individuals with cerebral palsy (CP) due to rectus femoris (RF) muscle spasticity. The Duncan-Ely test is a velocity-dependent measurement of spasticity that is recorded as positive or negative. At our institution, we use a modification of the Duncan-Ely test, a 5-point ordinal rating scale, which delineates where the catch occurs within the rapid arc of knee flexion. It has been named the Root-Ely test.

Questions/Purposes

We sought to determine the intra- and inter-rater reliability of the Duncan-Ely and Root-Ely tests in pediatric patients with CP.

Methods

A convenience sample of 20 ambulatory subjects was recruited; mean age was 10.5?±?4.5 years, and the Gross Motor Function Classification System (GMFCS) levels were I–III. Five clinicians measured each individual’s RF spasticity using the Root-Ely protocol during a single visit. Simple κ statistics with 95% confidence intervals (CI) were utilized for intra-rater reliability and weighted κ statistics with 95% CI for inter-rater reliability.

Results

The Root-Ely scale intra-rater reliability was 0.77 to 0.90 and inter-rater reliability was 0.32 to 0.87. Inter-rater reliability was good to excellent among experienced clinicians and fair to moderate in new clinicians.

Conclusion

The Root-Ely 5-point scale has acceptable intra- and inter-rater reliability in pediatric individuals with CP among experienced clinicians. The Root-Ely test allows experienced clinicians to reliably quantify severity of RF spasticity and may give orthopaedic surgeons a clinical tool to better predict ideal candidates for RF transfers in individuals with CP in order to improve stiff-knee gait.