Innovative Trial Designs, Multi-omics and Advanced Computational Prediction to Transform Clinical Care in RA

Rheumatoid arthritis (RA) is a complex, chronic disease of the immune system characterized by disfiguring and disabling arthritis. It affects predominantly women (3:1 ratio with men) and has its peak onset during their most productive years (ages 30-50). RA is associated with serious morbidity (including impaired fertility and pregnancy outcomes, disability, and depression) and premature mortality (particularly from cardiovascular and infectious causes). The Arthritis Alliance of Canada estimates that the cost of RA will exceed $30 billion in Canada in 2040.

First-line treatment of RA consists of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) with methotrexate considered as the gold standard. Yet, only 30% of patients will achieve adequate response to methotrexate and the majority will need additional treatment. The development of new biologic and targeted synthetic DMARDs (b/tsDMARDs) in the 20th century has transformed the treatment of RA. Anti-tumour necrosis factor (TNF)-α molecules were the first clinically successful biologic therapies for RA. Drugs targeting other signaling pathways (JAK-STAT, which work downstream of interferons), inflammatory cytokines (IL-6), as well as B cells and T cells have now also become available. Molecules with novel targets (eg. GM-CSF, CD40L) are in clinical trials.

Although hailed as 'game-changers' in patient care, the inconvenient truth is that even though nine different b/tsDMARDs are currently available to treat RA, 30% of patients will fail any particular drug. Moreover, physicians have no reliable way of predicting response and guiding treatment decisions. Clinical and genetic predictors have been the subject of intense research but these factors explain only a small portion of the observed variance in treatment response. Using the current trial-and-error approach, patients can cycle through multiple drugs before finally attaining disease control. This means months or years of suboptimal disease control and considerable losses in many domains including physical and emotional well-being, family and social networks, and occupational attainment. The lack of a personalized approach is particularly detrimental in RA because there is a narrow ''window of opportunity'' in the first 3-6 months of onset to control disease and optimize long term outcomes. In addition, failure to personalize treatment may also result in wasted spending on ineffective drugs, that cost up to $20,000 per patient per year, and exposing patients to unnecessary risks of adverse events, in particular serious infections.

There is a critical need to 1) transform the current 'trial-and-error' treatment paradigm, 2) explore novel predictors of b/tsDMARD response in RA and, 3) harness the power of advanced analytical strategies to personalize treatment decision-making and optimize outcomes in RA. The investigators propose a multi-pronged solution that combines innovative trial designs, multi-omics and advanced computational prediction to transform clinical care in RA.

The investigators propose to develop a new model of care and investigate new avenues, including sex and gender, diet, gut bacteria and environmental exposures, to make treatment decisions. The investigators will also use new methods of analyzing complex information. The highly talented research team has what is needed to transform the care of people living with RA.