Belimumab in SLE Synovial Inflammation and Lymph Nodes

Overview

Systemic lupus erythematosus (SLE)is an immune-mediated inflammatory disease (IMIDs) of which the cellular and molecular alterations of the immune system driving the diseases still remains largely unknown. Accordingly, it remains difficult to predict the individual patient's response to treatment. Moreover, the patient's response to treatment remains heterogeneous and difficult to predict, despite the development of a variety of novel and powerful drugs (including the so-called biologicals). Therefore, there is a clear need for the identification and validation of cellular and molecular biomarkers which can provide useful clinical information for diagnosis, classification, prognosis and treatment, as well as the development of new therapeutic strategies. Biomarkers can be found and analyzed in different body compartments, of which the peripheral blood and the intra-articular synovial fluid or tissue are most easily accessible. However, previous studies in RA and other IMIDs showed that adaptive immune responses in other tissues such as lymph nodes also play an important role. Investigating other immune compartments of the body such as the lymph nodes could result in new insights. To study the early pathogenesis of inflammatory conditions, in 2008 our department initiated core-needle inguinal lymph node biopsy sampling. Since then more than 100 lymph node biopsy procedures were performed. The procedure is well-tolerated and, other than a small hematoma which does not require therapy in most of the cases, no complications were reported. In the current study, the effects of belimumab (anti-BAFF) in SLE will be investigated by studying the immune alterations taking place in lymph nodes in comparison to peripheral blood and immune alterations taking place in the end-organ, e.g. the joint (wrist, knee or ankle) by taking synovial biopsies during a needle- or mini-arthroscopy. This procedure has been performed frequently in our department over the last 15 years. In this way immune alterations in the lymph nodes (secondary lymphoid organ), peripheral blood (systemic) and the joint (end organ for the disease) will be assessed and compared.

The primary goal of this study is to investigate the effects of belimumab on the composition of lymph nodes and the inflamed synovial tissue as well as (subsets of) immune cells in the peripheral blood using advanced flow cytometry methods. In addition, immunological alterations in lymphoid tissue and inflamed synovial tissue of SLE patients will be identified and correlated with disease stage/phenotype, prognosis, and belimumab treatment response. In this way novel biomarkers may be identified and validated that can be used for personalized medicine in SLE. The specific types of immunological alterations that will be studied include: * Genetic, epigenetic and transcriptional alterations of immune cells and stromal cells, including single cell RNA sequencing (scRNAseq) * TCR and BCR repertoire * Phenotype and function of (auto-reactive) T and B cells * Cytokine production by immune cells and stromal cells * Signalling events in immune cells and stromal cells * Antigen presentation by immune cells and stromal cells All of these parameters will be compared between lymph nodes, blood and synovium (if applicable) in SLE patients before and after belimumab treatment. Research Hypothesis Patients with SLE contain activated immune cells in their lymph nodes and inflamed synovial tissue. Furthermore, activation of stromal cells such as fibroblasts and endothelial cells may also be increased compared to (historical) healthy controls. In addition, dominant T cell and B cell clones may be present. Belimumab treatment will result in reduced inflammation in the synovial tissue and perhaps even normalization of lymph node architecture.