Thesis Bas Vastert: Mechanisms of disease and therapy in severe Juvenile Idiopathic Arthritis

Thesis: Mechanisms of disease and therapy in severe Juvenile Idiopathic Arthritis

Author: Bas Vastert, MD, PhD, pediatric rheumatologist. Center for Cellular and Molecular Intervention (professor Prakken) and department of pediatric rheumatology/immunology (professor Wulffraat), Wilhelmina Children’s Hospital, the Netherlands.

This thesis describes translational research in severe Juvenile idiopathic Arthritis (JIA), focusing on critical immunological features of both systemic (chapter 2-6) and polyarticular JIA (chapter 7-10).

SJIA is an auto-inflammatory disease, with a striking role for IL-1 as well as IL-6 and IL-18 mediated mechanisms in its pathogenesis and a strong association with macrophage activation syndrome (MAS), an acquired form of the hemophagocytic lymphohistiocytosis diseases.  In Chapter 3, we found an increased prevalence of heterozygous mutations in the perforin gene (PRF1) in sJIA patients with a history of MAS compared to sJIA without MAS, suggesting a role for PRF1 mutations in the development of MAS.

In chapter 4-6, we studied the apparent paradox of increased IL-18 (plasma) and deficient NK cell lytic function in sJIA. Physiologically, IL-18 is a strong stimulating factor of NK cell function. However, NK cells from sJIA patients failed to up-regulate cell-mediated killing molecules, such as perforin and interferon-gamma, after IL-18 stimulation in vivo and in vitro. We showed that the mechanism of impaired NK cell function in sJIA involves a defect in IL-18receptor (IL-18R) phosphorylation.

Chapter 5 and 6 describe a prospective cohort study in which we treated sJIA patients with recombinant IL-1 receptor antagonist (rIL-1RA or Anakinra) as first line therapy. We showed that early treatment with rIL-1RA resulted in normalization of IL-18 plasma levels. Moreover, we showed that rIL-1RA specifically restored the disturbed IL-18-NK cell axis by binding to the IL-18R besides its known effect on the IL-1 receptor. In chapter 6, we showed in a prospective observational study (20 new sJIA patients, mean follow up 32 months) that rIL-1RA is strikingly effective when started early in the disease (before the use of systemic steroids). Importantly, more than half of our sJIA patients were able to stop rIL-1RA treatment within 12 months with continued disease remission.

Chapter 7-10 focuses on the balance between regulatory T cells (Treg) and effector T cells in severe polyarticular JIA. In chapter 7, we tested the role of CD4+FOXP3+ Treg in a human model of induced acute inflammation: cardiac surgery. Subsequently, we studied the effect of therapeutic modalities on the Treg-Teffector balance in severe JIA (Methotrexate in chapter 8, anti-TNF in chapter 9 and autologous stem cell transplantation in chapter 10.  We found that both resistant Teff subsets and impaired function of Treg at the site of inflammation should be targeted in  severe polyarticular JIA.

Altogether, this thesis contributes to the understanding of key mechanisms underlying chronic inflammation in both systemic JIA and severe poly-articular JIA, as well as understanding how current therapeutic modalities can be used most efficiently to target this inflammation.

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