Treatment
Blocking T cell co-stimulation in primary Sjögren’s syndrome: rationale, clinical efficacy and modulation of peripheral and salivary gland biomarkers
E. Pontarini1, G.M. Verstappen2, S. Grigoriadou3, F.G. Kroese4, H. Bootsma5, M. Bombardieri6
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, UK.
- Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Centre Groningen, the Netherlands.
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, UK.
- Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Centre Groningen, the Netherlands.
- Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Centre Groningen, The Netherlands. h.bootsma@umcg.nl
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, UK. m.bombardieri@qmul.ac.uk
CER13885
2020 Vol.38, N°4 ,Suppl.126
PI 0222, PF 0227
Treatment
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PMID: 33095146 [PubMed]
Received: 01/08/2020
Accepted : 17/09/2020
In Press: 23/10/2020
Published: 23/10/2020
Abstract
There is accumulating evidence that patients with primary Sjögren’s syndrome (pSS) display aberrant CD4+ T cell responses, both in the peripheral compartment and in the inflamed salivary glands. CD4+ T cell abnormalities are also critically associated with B cell hyper activation, one of the hallmarks of disease, which is linked with disease severity and evolution to lymphoma. T cell activation and the cross-talk between T and B cells are tightly regulated by the balance between co-stimulatory pathways, such as the interactions between CD80/CD86:CD28, CD40:CD40L and ICOS:ICOSL, and co-inhibitory signals, including the immunoregulatory CTLA-4 protein. Evidence from patients with pSS as well as data from animal models of the disease suggests that these pathways play a critical role in pSS pathogenesis and their targeting could be exploited for therapeutic purposes. In this review, we first summarise the evidence implicating aberrant T cell co-stimulation and co-inhibition in driving the disease before focusing on the results of recent randomised controlled trials (RCTs) with compounds able to block T cell co-stimulation and enhance T cell co-inhibition. Despite a clear biological effect on downstream B cell activation has been observed in patients treated with CTLA-4-Ig (abatacept) and with monoclonal antibodies targeting CD40 and ICOSL, the clinical efficacy of this approach has so far yielded mixed results; while the anti-CD40 monoclonal antibody iscalimab showed significant improvement in systemic disease activity compared to placebo, two large RCTs with abatacept and a phase IIa RCT with an anti-ICOSL monoclonal antibody (prezalumab) failed to reach their primary endpoints. Although the discrepancies between biological and clinical efficacy of targeting T cell co-stimulation on pSS remain unresolved, several factors including drug bioavailability and receptor occupancy, patient stratification based on T-cell related biomarkers and the choice of study outcome are likely to play an important role and form the basis for further work towards the quest for a disease-modifying biologic therapy in pSS.
