An explorative study on deep profiling of peripheral leukocytes to identify predictors for responsiveness to anti-tumour necrosis factor alpha therapies in ankylosing spondylitis: natural killer cells in focus

Ursula Schulte-Wrede,Marta Steinbrich-Zöllner,Andreas Radbruch,Andreas Grützkau,Joachim Sieper,Uta Syrbe,Peihua Wu,Thomas Häupl,Till Sörensen,Denis Poddubnyy,Heike Hirseland,Joachim R Grün

doi:10.1186/s13075-018-1692-y

Abstract

BackgroundTherapeutic targeting of tumour necrosis factor (TNF)-α is highly effective in ankylosing spondylitis (AS) patients. However, since one-third of anti-TNF-treated AS patients do not show an adequate clinical response there is an urgent need for new biomarkers that would aid clinicians in their decision-making to select appropriate therapeutic options. Thus, the aim of this explorative study was to identify cell-based biomarkers in peripheral blood that could be used for a pre-treatment stratification of AS patients.MethodsA high-dimensional, multi-parametric flow cytometric approach was applied to identify baseline predictors in 31 AS patients before treatment with the TNF blockers adalimumab (TNF-neutralisation) and etanercept (soluble TNF receptor).ResultsAs the major result, the frequencies of natural killer (NK) cells, and in particular CD8-positive (CD8+) NK cell subsets, were most predictive for therapeutic outcome in AS patients. While an inverse correlation between classical CD56+/CD16+ NK cells and reduction of disease activity was observed, the CD8+ NK cell subset behaved in the opposite direction. At baseline, responders showed significantly increased frequencies of CD8+ NK cells compared with non-responders.ConclusionsThis is the first study demonstrating that the composition of the NK cell compartment has predictive power for prediction of therapeutic outcome for anti-TNF-α blockers, and we identified CD8+ NK cells as a potential new player in the TNF-α-driven chronic inflammatory immune response of AS.

Highlights

Therapeutic targeting of tumour necrosis factor (TNF)-α is highly effective in ankylosing spondylitis (AS) patients
All patients fulfilling the modified New York criteria [30] and who were eligible for anti-TNF inhibitor treatment because of persistently high disease activity (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) > 4) despite treatment with Non-steroidal antiinflammatory drug (NSAID) or who were unable to take NSAIDs due to contraindications were included in the study (Table 1)
Patient baseline characteristics and their clinical responses The study design encompassed 31 AS patients with high disease activity indicated by a baseline BASDAI of 6.2 ± 1.3 before treatment with adalimumab (ADA; n = 16) or etanercept (ETN; n = 15)

Summary

Introduction

Therapeutic targeting of tumour necrosis factor (TNF)-α is highly effective in ankylosing spondylitis (AS) patients. There are five anti-TNF-α agents approved for the treatment of AS: infliximab [9], a monoclonal chimeric antibody; etanercept, a soluble human TNF receptor (sTNFR) fusion protein [10]; adalimumab, a humanised monoclonal antibody [11]; golimumab, a fully human monoclonal antibody [12]; and certoluzimab, a Fab fragment of a humanised monoclonal antibody [13] Most of these biologics are successfully administered in rheumatoid arthritis (RA), psoriasis (Pso), juvenile inflammatory arthritis (JIA), and inflammatory bowel disease (IBD). TNFR2 can be found to be expressed in endothelial and mesenchymal cells, cells of the central nervous system (CNS), oligodendrocytes and cardiac myocytes [17], and a few other cell types [18] According to their functions, TNFR1 is primarily associated with pro-apoptotic processes, while TNFR2 is responsible for processes ensuring survival of cells [19]

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