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

Elena Pontarini, Gwenny M Verstappen, Sofia Grigoriadou, Frans G M Kroese, Hendrika Bootsma, Michele Bombardieri

Research output: Contribution to journalReview articlepeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)222-227
Number of pages6
JournalClinical and Experimental Rheumatology
Volume38 Suppl 126
Issue number4
Publication statusPublished - 1-Jul-2020

Keywords

  • Animals
  • Humans
  • Lymphocyte Activation
  • Salivary Glands
  • Sjogren's Syndrome/drug therapy
  • T-Lymphocytes
  • Treatment Outcome

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