IL-7 in Rheumatoid Arthritis: Pathogenesis, Biomarker and Rationale for Anti-IL-7 Therapy

Rheumatoid arthritis (RA) is a chronic disease primarily affecting the joints and producing marked inflammatory changes in the synovial membrane and adjacent structures. Although any joint can be affected the disease normally affects the hands, feet, knees and wrists. Disease activity and the rate of progression to involve new joints are variable. The pain and disability associated represent a real burden both for the patients and society and the disease is also associated with premature mortality [1, 2]. There is currently no cure for RA. Historically, treatments which deplete T-cells led to reduction of symptoms supporting the notion of a T cell mediated disease. Today, the pathology is thought to be the product of a series of complex cellular interactions where synovial T-cells orchestrate disease through their interaction with fibroblasts, B-cells, dendritic cells, and macrophages. Modern treatment options include the use of “biological” drugs, which block cytokines such as TNF alpha, IL-1, IL-6, limit costimulation between B and T-cells or deplete B-cells. Although their use bring great benefit, a wide range of adverse events have been reported (including infections, cancer, vasculitis, lupus-like and multiple sclerosis, liver disease, hematologic abnormalities (such as aplastic anemia, lymphoma) and aseptic meningitis). In addition resistance to these agents or loss of response, relapse on cessation of treatment, side effects occurs in more than 40% of patients. The cost of these therapies is also major pitfall.  Corresponding author: Dr. Frederique Ponchel, Email: mmefp@leeds.ac. uk. No part of this digital document may be reproduced, stored in a retrieval system or transmitted commercially in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services. Frederique Ponchel, Agata Burska, Effie Myrthianou et al. 32 The complex cellular interactions in the synovium between stromal cells, T-cells and their subsequent effect on B-cells, macrophages and endothelial cells provide a large panel of alternative targets, both cellular and molecular, for therapeutic intervention in RA. Inhibiting cytokines signalling has proven successful and we (and others) hypothesise that IL-7 may be an appropriate therapeutic target in RA as well as in several other autoimmune diseases. The main rational for targeting IL-7 is that it is (i) over expressed specifically at the disease site, however only in active disease, (ii) not capable of exiting the joint (due to its retention and presentation by extra-cellular matrix) (iii) produced by local resident cells with no mobility (i.e. fibroblasts). In addition, low levels of circulating IL-7 in RA patients suggest that efficient inhibition of IL-7 signalling may only take place in the joint. The role of IL-7 in the disease itself is slowly being dissected and will be reviewed to support this statement.