The prevalence of axial spondyloarthritis in the UK: a cross-sectional cohort study

Background: Accurate prevalence data are important when interpreting diagnostic tests and planning for the health needs of a population, yet no such data exist for axial spondyloarthritis (axSpA) in the UK. In this cross-sectional cohort study we aimed to estimate the prevalence of axSpA in a UK primary care population. Methods: A validated self-completed questionnaire was used to screen primary care patients with low back pain for inflammatory back pain (IBP). Patients with a verifiable pre-existing diagnosis of axSpA were included as positive cases. All other patients meeting the Assessment of SpondyloArthritis international Society (ASAS) IBP criteria were invited to undergo further assessment including MRI scanning, allowing classification according to the European Spondyloarthropathy Study Group (ESSG) and ASAS axSpA criteria, and the modified New York (mNY) criteria for ankylosing spondylitis (AS). Results: Of 978 questionnaires sent to potential participants 505 were returned (response rate 51.6 %). Six subjects had a prior diagnosis of axSpA, 4 of whom met mNY criteria. Thirty eight of 75 subjects meeting ASAS IBP criteria attended review (mean age 53.5 years, 37 % male). The number of subjects satisfying classification criteria was 23 for ESSG, 3 for ASAS (2 clinical, 1 radiological) and 1 for mNY criteria. This equates to a prevalence of 5.3 % (95 % CI 4.0, 6.8) using ESSG, 1.3 % (95 % CI 0.8, 2.3) using ASAS, 0.66 % (95 % CI 0.28, 1.3) using mNY criteria in chronic back pain patients, and 1.2 % (95 % CI 0.9, 1.4) using ESSG, 0.3 % (95 % CI 0.13, 0.48) using ASAS, 0.15 % (95 % CI 0.02, 0.27) using mNY criteria in the general adult primary care population. Conclusions: These are the first prevalence estimates for axSpA in the UK, and will be of importance in planning for the future healthcare needs of this population. Trial registration: Current Controlled Trials ISRCTN7687321

The prevalence of inflammatory back pain in a UK primary care population

Inflammatory back pain (IBP) is the earliest and most common symptom of axial SpA. However, there is very little information about the prevalence of IBP in the UK. In this cross-sectional cohort study we examined the prevalence of IBP in a UK primary care population using three published IBP criteria

A Strategy to Assess the Cellular Activity of E3 Ligases against Neo-Substrates using Electrophilic Probes

Targeted protein degradation promises to enable small molecule-mediated modulation of currently undrugged proteins. While the well-characterized E3 ligases CRBN and VHL have successfully promoted the degradation of many proteins of interest, there are approximately 600 additional E3 ligase family members that may offer improved activity, substrate selectivity, or tissue distribution; however, characterizing the ability of these many ligases to promote targeted protein degradation has proven challenging. Here, we report the development of a rapid method to evaluate the ability of recombinant E3 ligase components to support the degradation of neo-substrates. Bypassing the need for hit finding to identify specific E3 ligase binders, this approach makes use of simple chemistry for Covalent Functionalization Followed by E3 Electroporation into live cells (COFFEE). We demonstrate this method using covalent E3-target binder complexes of VHL-JQ1 and VHL-dasatinib and show the degradation of Brd4 and Lyn kinase, respectively. Applying COFFEE to SPSB2, a SOCS box and SPRY-domain E3 ligase not previously shown to degrade neo-substrates, we demonstrated the ability of this method to rapidly validate an uncharacterized ligase for degradation of neo-substrates

A Strategy to Assess the Cellular Activity of E3 Ligase Components against Neo-Substrates using Electrophilic Probes

Targeted protein degradation is a rapidly developing therapeutic modality that promises lower dosing and enhanced selectivity as compared to traditional occupancy-driven inhibitors, and the potential to modulate historically intractable targets. While well-characterized E3 ligases such as CRBN and VHL have been successfully redirected to degrade numerous proteins, there are approximately 600 predicted additional E3 family members that may offer improved activity, substrate selectivity, and/or tissue distribution. Characterizing the potential applications of these many ligases for targeted protein degradation has proven challenging. Here, we report the development of an approach to evaluate the ability of recombinant E3 ligase components to support neo-substrate degradation. Bypassing the need for hit finding to identify specific E3 ligase binders, this approach makes use of simple maleimide-thiol chemistry for Covalent Functionalization Followed by E3 Electroporation into live cells (COFFEE). We demonstrate this method by electroporating recombinant VHL, covalently functionalized with JQ1 or dasatinib, to induce degradation of BRD4 or tyrosine kinase targets, respectively. Furthermore, by applying COFFEE to SPSB2, a Cullin-RING ligase 5 receptor, as well as to SKP1, the adaptor protein for Cullin-RING ligase 1 F-box (SCF) complexes, we validate this method as a powerful approach to define the activity of previously uncharacterized ubiquitin ligase components, and provide further evidence that not only ligase receptors but also adaptors can be directly hi-jacked for neo-substrate degradation