System Investigation of Biologic Effects of Rheumatoid Arthritis Treatments using Phenotypic Profiling

This webinar will examine how investigating biologic effects of combination treatments can be conducted with an in vitro phenotypic profiling platform, using rheumatoid arthritis combination treatments as an example.

The objective of current standard of care for rheumatoid arthritis (RA) is to maintain disease remission or low disease activity through suppression of inflammation. Unfortunately, this is rarely achieved through treatment of a single treatment, so combinations of treatments are commonly used. However, combination treatments often reflect physician preference rather than scientific rationale with the single exception of methotrexate, which has been shown to reduce immunogenicity of TNF-alpha inhibitors, especially infliximab and adalimumab (ADA).

In this webinar, we will discuss:

• How to utilize the BioMAP® phenotypic profiling platform to investigate the pharmacodynamic interactions of methotrexate and adalimumab versus Tocilizumab in RA treatment.
• Share results that suggest a systematic evaluation of potential pharmacodynamic interactions can inform on addition or synergistic combination therapy in diseases such as RA.
• Present a powerful approach to investigate combination treatments in vitro while obtaining insight into in vivo behaviour of treatments for improved patient outcomes.

Globally, rheumatoid arthritis (RA) is the most common chronic inflammatory arthritis afflicting 0.5% of the population. Chronic inflammation leads to destruction of cartilage and bone resulting in joint deformity and physical disability. Suppression of inflammation is important to prevent joint damage. Therefore, the objective of current standard of care is to maintain disease remission or low disease activity. This is rarely achieved by treatment with one Disease Modifying Anti-Rheumatic Drugs (DMARDs), so combination of DMARDs are commonly used.

Over the last two decades, five classes of biologic agents have been licensed for the treatment of rheumatoid arthritis (RA): tumour necrosis factor alpha (TNF-alpha) inhibitors, interleukin (IL)-1 inhibitors, depleters of B cells, T cell co-stimulation blockers and IL-6 inhibitors. These treatments are effective but expensive. Clinical guidelines recommend combining treatment by biological agents with methotrexate (MTX) based on evidence from randomised control trials of MTX and TNF-alpha inhibitors demonstrating superiority of the combination over monotherapy. Although combinations of DMARDs are commonly used to treat RA, these reflect physician preference rather than scientific rationale with the single exception of MTX, which has been shown to reduce immunogenicity of TNF-alpha inhibitors especially infliximab and adalimumab (ADA). It has been assumed that this effect is the sole reason why combining MTX with TNF-alpha inhibitors is superior to TNF-alpha inhibitors monotherapy. Interestingly, combining MTX with the anti-IL-6R monoclonal antibody Tocilizumab (TCZ) did not show the same degree of additive benefit when compared with TCZ monotherapy.

Using the BioMAP phenotypic profiling platform from DiscoverX, potential pharmacodynamic interactions between MTX and ADA versus TCZ were investigated. Results from the phenotypic profiling suggested significant greater pharmacodynamic interactions between MTX and ADA versus TCZ. Interestingly, BioMAP phenotypic profiling demonstrated MTX has a significant inhibitory effect on production of immunoglobulin by B cells, which explains the ability of MTX to reduce immunogenicity of therapeutic monoclonal antibodies. These data are consistent with clinical experience that the magnitude of benefit when MTX plus ADA is greater than either as a monotherapy and less additive benefit when MTX is combined with TCZ. The result of this study suggest systematic evaluation of potential pharmacodynamic interactions can inform on addition or synergistic combination therapy in diseases such as RA.

The BioMAP phenotypic profiling systems contain one or more early passage human primary cell types that are cultured in standardized stimulatory conditions designed to simulate tissue states and signaling networks relevant to physiological biology in an in vitro format. Each BioMAP system quantitatively measures biomarker readouts (7 – 24 per system) that are selected for therapeutic and biological relevance, are thought to be predictive for disease outcomes or specific drug effects and are validated with characterized agents with known mechanism of action. More than 50 BioMAP systems have been developed to cover a range of disease-related biology that are relevant to different medical conditions.

Speaker

Ernest Choy, MD, FRCP, Head of Rheumatology, Section of Rheumatology, Institute of Infection and Immunity, Cardiff University, Cardiff, United Kingdom

Professor Ernest Choy is Head of Rheumatology and Translational Research at the Institute of Infection and Immunity and Director of the Cardiff Regional Experimental Arthritis Treatment and Evaluation (CREATE) Centre at Cardiff University School of Medicine, UK. He is also Honorary Consultant Rheumatologist at University Hospital of Wales and Clinical Lead of the Welsh Arthritis Research Network (WARN). His major research interest is the treatment of rheumatic diseases focusing on efficacy of new treatment strategies. Prof Choy is a member of the European League Against Rheumatism Committee Standing Committee for International Clinical Studies Including Therapeutic Trials. He chairs the EULAR Taskforce on developing recommendations for management and classification criteria for fibromyalgia. Prof Choy has served as clinical expert to the National Institute for Clinical Excellence in the UK and many Pharmaceutical companies. He has published widely on treatments for rheumatic diseases in major medical journals and is a frequent lecturer on the treatment of rheumatic diseases.

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