A simple blood test could determine which biologic drug will work best for a person with psoriatic arthritis, replacing the current trial-and-error approach. Around 150,000 people in the UK have psoriatic arthritis, an inflammatory condition that damages joints. About half of these patients eventually need biologic drugs, but current first-line options—TNF inhibitors and IL-17 inhibitors—each work in only about 50% of patients. Doctors have no way to predict which drug will help which patient, so people often cycle through ineffective treatments while their disease progresses. This trial will test whether measuring a specific immune cell type—activated Th17 cells—in a patient’s blood can guide drug selection. Patients will be stratified by their Th17 level and randomly assigned to receive either a TNF or IL-17 inhibitor. The researchers will track how many achieve minimal disease activity after 24 weeks, then model whether this precision approach would outperform standard care in routine practice. If successful, the biomarker could be developed into a companion diagnostic test, allowing clinicians to match patients to the right biologic from the start. Because both drug classes are already approved for psoriatic arthritis, implementation could be rapid, potentially changing treatment guidelines and sparing thousands of patients months of ineffective therapy.
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Research Question: Can peripheral immunophenotype predict response to biologics in psoriatic arthritis (PsA)? Background: PsA is an inflammatory arthritis occurring in ~15% of people with psoriasis, affecting ~150,000 people in the UK. The current treatment of PsA follows a ‘step up’ approach using different conventional disease-modifying drugs followed by biologics if patients do not respond. Around 50% of patients require biologics. The current first line biologics for PsA target two main immunological pathways: tumour necrosis factor (TNF) or interleukin-17 (IL-17). Response rates for both are similar with the target of treatment achieved in ~50% of patients; however response cannot currently be predicted. A recent proof of concept study in PsA suggested that using peripheral immunophenotype to choose therapy could improve clinical outcomes over standard care. Aims and objectives: In workstream (WS) 1, we will test the hypothesis, within a biomarker-stratified randomised controlled trial, that the baseline CD4 T cell activated Th17 immunophenotype predicts response to IL-17 and/or TNF inhibitors in PsA. We will validate the biomarker and optimal threshold (activated Th17>1.58%) for selecting therapy. In WS 2, additional analyses will identify if the model can be optimised by combining clinical (disease duration, psoriasis, enthesitis) and immunophenotypical (intracellular CD4 Th17 frequency, CD8 Tc17 frequency, MAIT cell frequency, immune transcriptomics) factors. We will use statistical modelling to predict the likely effectiveness of these precision medicine approaches compared to standard of care. In WS 3, we aim to further elucidate the mechanistic basis of psoriatic disease and the differential response to biologics by examining surface, intracellular and transcriptomic signatures in whole blood and immune subsets and establish a biobank for future mechanistic studies. Methods: Patients with PsA eligible to start their first biologic will be recruited and baseline blood tests taken to assess their peripheral immunophenotype. They will be stratified equally by Th17 levels and randomised 1:1 to receive either TNF or IL-17 inhibitors. The primary analysis will establish the interaction between baseline immunophenotype and treatment on the primary outcome (proportion achieving the minimal disease activity criteria at week 24). Statistical modelling will be used to estimate how effective this approach could be in routine clinical practice. In secondary analysis, modelling will identify if this prediction model can be optimised further incorporating clinical phenotypes of disease and additional immunophenotyping techniques. Timelines for delivery: The grant is proposed to start in April 2020 with first patient first visit by 1st January 2021 and all centres recruiting by 1st April 2021. Recruitment will be over 18 months with 6 months follow up, allowing 1 year for analysis, including statistical modelling and a final 3 months for publication and dissemination. Anticipated impact and dissemination: The analysis will model the likely effectiveness of a precision medicine approach and could impact on future care rapidly as both drug classes are already approved in this indication. The proven biomarkers will be developed as a companion diagnostic to enable delivery in clinical practice. Dissemination will be via conference presentations and peer reviewed publications, potentially impacting on treatment guidelines.
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