Novel therapeutics – exciting gifts but how best to use them?

These are the most exciting times to be a rheumatologist! The therapeutics of rheumatoid arthritis (RA) have changed dramatically in the last decade with the arrival of novel biologic-based medicines. However, an even more significant impact on outcomes has arisen from the radical change in approach to the treatment of the disease embodied in ‘treatment to target’, specifically the relentless pursuit of a low disease-activity state in clinical practice. In one sense, we have learned much about how to optimally utilise our existing conventional disease-modifying anti-rheumatic drugs (DMARDs). Thus, a formal strategic approach to care, combined with regular assessment of the actual level of disease activity, however measured, has resulted in a significant proportion of patients achieving substantial improvements in their overall quality of life. Critically, however, few patients are yet reaching sustained remission as assessed by metrics of clinical disease activity – even fewer are in remission if more stringent imaging criteria are applied. Thus, RA remains a chronic disease with attendant co-morbidity and a requirement a priori for long-term continuous administration of pharmaceutical agents.

Understanding pathogenesis is considered of pivotal importance in evolving future improved therapies. Recent genome-wide analyses, together with extensive functional studies in the post-genomic arena, have clearly defined RA as a disease of autoimmunity. Pre-articular disease associated with co-morbidities leads via a transitional event (as yet ill-defined) to the development of inflammatory synovitis and the classical RA presentation familiar to rheumatologists. The factors that drive the acute-to-chronic switch in the synovial compartment are entirely unclear. Such factors will likely be of rich therapeutic utility. Meantime, several principles have emerged. Early treatment, apparently regardless of agent, leads to improved proportional outcomes that are usually of higher magnitude. This suggests that a ‘window of opportunity’ may exist when pathogenetic pathways are labile to reversal and immune homeostasis may be recoverable. More aggressive regimens, regardless of agent chosen, also lead to preferential outcomes – no consensus, however, yet exists as to whether these should be of a step-up or combination step-down variety. The aspiration of the discipline should now be to move towards remission induction and maintenance with a longer-term view on maintaining such low-disease states in the absence of continuous agents – the latter would represent the achievement of a state of immunological tolerance. Curiously, although pathogenesis-based discoveries have driven the advent of new therapeutics, they do not yet promote the utilisation of the same. Therefore, we use medicines in the order of discovery and licensing rather than driven by a pathological evaluation of the optimal time for a given mode of action to impact on disease. Biomarkers and a new molecular taxonomy of disease will facilitate the latter in due course but, meantime, it seems beyond routine clinical care.

Amidst the foregoing rapidly evolving field, this edition of the journal brings together an outstanding international group of experts in the field who, together, provide an authoritative overview of the state of the art in the current and novel therapeutics. Insights into the current use of cell-targeting and cytokine-modulating medicines reside alongside future directions in which matrix and bone/cartilage biology are considered for their therapeutic potential. Cellular therapies and the possibility that we could achieve useful stem cell-based approaches are discussed. The possibilities in therapeutic immune tolerance are evaluated with intriguing lessons to be learned across disciplines. Existing and future strategies in which these novel modalities might be employed are described. We commend these overviews to you since they clearly illustrate that the future may be an even more exciting time to be a rheumatologist!

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Nov 11, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Novel therapeutics – exciting gifts but how best to use them?

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