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Blocking T cell co-stimulation in primary Sjögren’s syndrome: rationale, clinical efficacy and modulation of peripheral and salivary gland biomarkers


1, 2, 3, 4, 5, 6

 

  1. Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, UK.
  2. Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Centre Groningen, the Netherlands.
  3. Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, UK.
  4. Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Centre Groningen, the Netherlands.
  5. Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Centre Groningen, The Netherlands. h.bootsma@umcg.nl
  6. 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.

Rheumatology Article