Current Topics in Medicinal Chemistry - Volume 13, Issue 6, 2013

Rheumatoid arthritis (RA) is the most frequent form of chronic polyarthritis, affecting 0.5-1% of adults worldwide. In recent years there have been important advances in the pathogenesis of RA, together with new diagnostic and therapeutic insights. Early diagnosis is essential in order to prevent joint damage and improve the prognosis and quality of life of patients with RA. New classification diagnostic criteria have been proposed to achieve this objective. New therapeutic strategies have proved to be effective, including early and better use of synthetic disease-modifying anti-rheumatic drugs (DMARDS), mainly methotrexate, and a treat-to-target strategy focusing on achieving remission and with tight control of the disease. In the last decade, the introduction of various biological agents in the therapeutic armamentarium of RA has changed the disease prognosis, although no definite cure is currently possible. In this chapter, we present an overview of recent advances in the epidemiology, diagnosis, prognosis and treatment of this severe but treatable disease.

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases. Genetic and epidemiologic studies point to a relevant role of adaptive T-cell response interactions with environmental factors such as smoking in the immunopathogenesis of the disease. These interactions result in a specific systemic autoantibody response that seems to contribute to the synovial inflammatory process. The reasons for specific localization of the autoimmune proinflammatory process to synovial tissue remain poorly known, but relevant local effector mechanisms have been recently unveiled and successfully targeted by new specific therapies. A relevant role for cytokine networks, where TNF-α displays a pivotal role, has been confirmed. The local pathology is hallmarked by immune cell accumulation and expansion of resident stromal and vascular cells. Crosstalk between these elements generates an aggressive environment that leads to cartilage and bone destruction. RA provides represents a model for systemic T-cell mediated systemic autoimmunity leading to local cellular and autoantibody mediated chronic inflammation. Whereas targeting of these elements with specific antagonists may interfere with the disease process, reestablishing tolerance and preventing further synovial inflammation has not been achieved.

Rheumatoid Arthritis (RA) is a chronic autoimmune inflammatory disease that affects largely synovial joints. It has been postulated that activated autoreactive CD4 T cells play a key role in triggering and-or maintaining the chronic inflammatory process in RA. Dendritic cells (DCs) are antigen-presenting cells that activate cognate clonal CD4 T cells in the lymph nodes. The activation process involves the formation of a molecular structure at the DC-CD4 T cell contact zone called immunological synapse (IS). In RA, the synovium, a thin layer of tissue below the capsule in the joints, shows a massive infiltration of DCs and CD4 T cells. Subjects bearing HLA-DRB1 alleles of the Major Histocompatibility Complex II gene displaying a motif called RA “shared epitope (SE)”, have an enhanced susceptibility to suffer RA. Interestingly, the SE-containing HLA-DRB1 molecules display a pocket with a high affinity for citrullinated antigens, which are found at higher levels in subjects prone to develop RA. Thus, it is possible that the DCs of susceptible individuals may form IS with particular features that may present citrullinated peptides to autorreactive naïve CD4 T clones that, after being activated, contribute to the initiation or development of the disease. Herein I put forward a model of RA initiation based on current information on the immune response and RA.

Rheumatoid Arthritis (RA) is the most common chronic inflammatory disease of the joints and is characterized by a complex genetic architecture. In recent years, a substantial advance has been performed in the identification of the genes that increase the risk to develop RA. Genome-Wide Association Studies (GWAS) have allowed the characterization of more than 40 new susceptibility genes and the confirmation of a marked differential genetic background between patients expressing anti-cyclic citrullinated peptide antibodies (ACPA, approximately 80% of all RA patients) and ACPA negative RA patients. GWAS have also confirmed the existence of a common genetic basis between RA and other autoimmune diseases and the overrepresentation of specific biological pathways like antigen presentation and TNF signaling. Dense genotyping analysis has also allowed the detailed characterization of the different association signals within the HLA region, the strongest risk locus for RA. In the present manuscript, we also review the most recent advances in the genetics of clinically relevant subphenotypes in RA which are the response to treatment and the severity of the disease. In the next years the increasing ability to characterize the DNA variation and the availability of well characterized patient cohorts will be critical to translate genetic information into the much awaited personalized medicine in RA.

Effective management of Rheumatoid Arthritis (RA) is being hampered by the difficulties for its early diagnosis and the heterogeneity of the disease. Although early intervention can result in disease remission, it requires early diagnosis, and current diagnostic tests are not sufficiently accurate or sensitive in the early stages of RA. Therefore, research efforts are increasingly focused on gaining knowledge about RA pathogenesis, and also on the discovery of novel biological markers that enable early diagnosis and stratification of the disease, and thus the implementation of targeted therapies. Ongoing research includes the emergence of novel approaches for the characterization of molecules that play a role in RA, such as genomic, proteomic and metabolomic technologies. These techniques, coupled with sophisticated statistical methods, permit the simultaneous analysis of multiple targets, and have become very powerful tools in RA research both for etiopathogenesis studies and biomarker discovery. It is believed that proteomics will soon provide a much-needed novel therapeutic approach to treating RA. This chapter will focus on the utility of Proteomics in RA research to enable a better understanding of the disease process, and to provide novel protein biomarkers useful for early diagnosis, prognosis and the application of tailored treatments.

Antibodies directed against citrullinated proteins and peptides (ACPAs) are the most specific serological markers available for diagnosing rheumatoid arthritis (RA). ACPAs may be detected several years before symptoms of RA appear, and their presence at disease onset is a good predictor of the development of erosive joint lesions. RA patients can be classified into two major groups: those who have ACPAs and those who do not. The presence of ACPAs at early stages of RA predicts the development of earlier and more widespread joint erosions, and low remission rates. Synthetic peptides can replace cognate proteins in solid-phase assays for specific autoantibody recognition in RA patients. The use of synthetic peptides instead of proteins represents an advantage in terms of the reproducibility of such immunoassays. Proteins also contain non-citrullinated epitopes that are recognized by non-RA sera and this could reduce the specificity of the test. The use of synthetic citrullinated peptides gives absolute control over the exact epitopes presented. Furthermore, it is difficult to prepare sufficient amounts of high-quality antigenic proteins with a well-defined degree of citrullination. Synthetic citrullinated peptides, in contrast, are easily obtained in a pure form with a well-defined chemical structure and the epitopes can be precisely oriented in the plate by covalent binding of the peptides. Chimeric peptides bearing different citrullinated protein domains have recently been used in the design of RA diagnosis systems. The results of the application of those systems indicate that more than one serological test is required to classify RA patients based on the presence or absence of ACPAs. Each of the target molecules reported (fibrin, vimentin and filaggrin) helps to identify a particular subset of RA patients.

Biologic therapies have notably improved the treatment of RA, making disease remission a realistic goal. After more than ten years of experience, the safety issues associated with these drugs are well characterized and can be avoided with careful patient selection and tight clinical control. Although the different biologic drugs (anti-TNF agents, anti-IL-6, anti-B cells and anti-costimulation of T-cells) have apparently different mechanisms of action, all biologic agents have demonstrated similar efficacy. In addition results of the combination of two biologic therapies have shown no additive clinical effects, although there is an increased risk of infection. Therefore, further research is needed to optimize the use of these and future targeted therapies in RA.

Tyrosine kinases (TK) are enzymes capable of transferring phosphate groups to tyrosine residues in cytoplasmic proteins or the intracellular domains of transmembrane receptors. TK play critical roles in diverse biological functions including cellular processes such as adhesion, motility, proliferation, cell cycle control, cell death, as well as biological functions at the whole-organism level such as growth and development, metabolism or immune defense. TK inhibitors including spleen TK (fostamatinib) and Janus kinases (tofacitinib) inhibitors are two novel oral therapies that have demonstrated short-term good clinical responses in active rheumatoid arthritis patients with and inadequate responses to methotrexate or other traditional (non-biologic) disease-modifying antirheumatic drugs (DMARDs). Those responses are comparable to responses rates from pivotal trials of TNF inhibitors. TK inhibitors are generally well tolerated but not free of adverse effects. Several side effects had been described including gastrointestinal symptoms, neutropenia, hypertension, elevated liver function test and lipid alterations among others. Owing to the limited duration of follow-up of patients treated with TK inhibitors, the long term safety profile of these drugs are unknown.