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Rheumatic and musculoskeletal diseases (RMD) affect over 120 million EU citizens, at an estimated cost of €240 billion, with direct costs of 2 per cent EU GDP. Rheumatoid arthritis (RA) is an important chronic RMD worldwide, causing significant ill-health, disability and increased mortality in 1-to-2 per cent of the population. It affects more women than men, and often more severely. It is also most common between the ages of 40 and 70, but it can affect people of any age, including children. RA results in reduced quality of life and increased comorbidity, such as atherosclerosis, cardiovascular disease, diabetes and obesity. RA disability stems from structural damage of cartilage and bone due to erosions in synovial joints, if not treated early and aggressively.
Increased synovial inflammation is critically involved in inducing bone loss in RA. However, we cannot currently predict who will develop bone erosions. Conventional imaging with plain radiographs do not detect inflammation or structural damage until after it has occurred, when it may be too late. In addition, biomarkers of damage are insensitive and may only be detectable at a late stage. RA is a heterogeneous disease and outcome is patient-specific.
Targeted biologic therapies, including TNF inhibitors (TNFi), have shown significant benefits on the outcome of RA, however 30-to-40 per cent of patients have suboptimal responses or suffer adverse events. The cost of RA therapy in Ireland, including biologic therapies, is over €19,000 per patient per year, therefore 30 per cent of patients will receive expensive therapy destined to fail. Trial and error of expensive, high-tech medications is not a cost-effective strategy, especially when we know that a high percentage of RA patients will not respond adequately. Indeed, only one-in-four patients reach true remission.
One of the biggest difficulties with treating the condition is early diagnosis. With early diagnosis and aggressive treatment, it is possible to reduce the damage to the joints caused by RA. Furthermore, deciding the most appropriate treatment for each patient at disease onset is critical to effectively treating the disease and the best outcome for patients. Currently, there is limited information with which we can accurately predict who will develop more severe and erosive disease or who will respond to the current treatment strategies. Most patients start on conventional oral medicine for six months before specific biologic therapy can be introduced. In addition, as new therapies are developed, there does appear to be an enhanced possibility of long-term response and ultimately, we are looking for a cure.
Trial and error of expensive, high-tech medications is not a cost-effective strategy, especially when we know that a high percentage of RA patients will not respond adequately. Indeed, only one-in-four patients reach true remission
The most recent research suggests that autoantibodies and specific features on the joint tissue biopsy may predict severe and erosive disease that will respond to specific monoclonal antibody therapy. Not all patients respond to every treatment, and of those who do, finding the right treatment can be a process of trial and error. A patient might be put on two or three different medications before responding to one; by that time, damage and/or functional disability may have developed. Therefore, current research strategies are focused on identifying biomarkers to allow for identification of patients who will respond to specific treatment at the onset of disease, to predict disease outcome, and to identify new therapeutic strategies for patients who do not respond to current treatments.
The presence of anti-citrullinated peptide antibodies (ACPA) in the blood of patients with RA may provide improved prediction of outcome in RA. In recent years, several studies suggest that first-order stratification of RA should be based on the presence or absence of rheumatoid factor (RF) and ACPA in sera. ACPA is detected using artificial antigen by anticyclic-citrullinated peptide (anti-CCP) assays, and appears to be highly specific to RA. Indeed, these antibodies may be present before the onset of clinical arthritis, in some cases several years before, suggesting that autoimmunity precedes inflammation.
In addition to predicting susceptibility, there appears to be an increased prevalence of bone damage in ACPA-positive RA patients that suggests a relationship with disease severity. Thus, a direct link between autoantibody response and structural bone damage in RA may exist, however, the mechanisms involved are not clearly understood.
We have recently examined synovial tissue inflammation according to whether patients are positive or negative for ACPA in a large group of RA patients and examined response to treatment and erosive status. We demonstrated significantly higher inflammation of joint tissue — synovium — in RA patients who were positive for ACPA compared to those that were negative. This increased inflammation was characterised by significantly higher numbers of immune cells, specifically B cells and T cells. Furthermore, aggregates of B cell infiltrates into the joint tissue were higher in ACPA+ patients with erosions demonstrated at follow-up, which was also associated with an increase in levels of a serum protein called CXCL13 that specifically attracts B cells.
Therefore, this study suggests that identifying RA patients that are ACPA+ at an early stage of disease and in those at risk of developing RA will inform the clinician to target RA more aggressively. In addition, the association between ACPA positivity and increased numbers of B-cells suggests that these patients may benefit from starting on rituximab treatment (anti-B cell monoclonal antibody therapy) rather than methotrexate followed by anti-TNF therapy. This type of approach will help to develop a more personalised approach of ‘precision medicine’ through stratification, which should enable us to know which treatment a patient will respond to first time round.
Models of arthritis
Research at the Department of Molecular Rheumatology, Trinity College Dublin, and the Centre for Arthritis and Rheumatic Disease, University College Dublin, has developed novel models of arthritis that allow the scientists and doctors to identify and test potential new therapeutic targets before they are brought into clinical trials. This is specifically focused on the cells at the site of inflammation.
Activation of inflammation in our cells is a key mechanism by which our body fights infection. However, if uncontrolled, the inflammatory cells do not switch off and this can contribute to development of autoimmune diseases. In the joints of patients with RA, many new blood vessels grow, allowing immune cells from the blood to invade into the joint, leading to increased joint inflammation and destruction of cartilage and bone.
We have shown a dramatic change in the metabolic activity of synovial cells due to an increased demand for energy under-activated conditions in the synovium of patients with RA. This enables synovial cells to generate sufficient energy, in the form of ATP, to support enhanced synovial cell activation and invasion. We have also identified key proteins that mediate these pathways in specific cell subtypes, such as fibroblasts, macrophages and dendritic cells, all of which are key to driving the inflammatory response in RA.
By using specific inhibitors and synovial cells from patients with RA, we have been able to metabolically reprogramme these cells, in the laboratory, to one of normal homoeostasis. Switching the metabolic profile of synovial cells inhibited cell invasiveness and key proteins involved in inflammation (Biniecka et al, Dysregulated bioenergetics: A key regulator of joint inflammation. Ann Rheum Dis, 2016 Dec;75(12):2192-2200), thus targeting metabolic pathways, may provide a new therapeutic strategy.
RMD are common across the EU and globally, with RA being the most notable cause of illness and long-term joint damage. The biologic treatments such as TNFi have improved the responses for many, but not all, patients. The current research focus is on new biomarkers to stratify and define patients who will effectively respond to one of the newer therapies from the outset.
RMD in general and RA specifically are, however, chronic diseases that can affect a wide range of people, mainly young women, but also children and men. Some biomarkers such as ACPA have been identified, even before disease presents clinically and along with joint biopsies, these may predict outcomes more accurately — including response to therapy. Novel drug therapies continue to be developed to attempt to identify more effective and less-toxic drugs that will improve outcomes. The main focus of new therapies remains to find the elusive ‘cure’.