Using the “potential-outcomes framework” to predict added value of more intensive initial therapy for individual early Rheumatoid Arthritis (RA) patients

Rheumatoid Arthritis (RA) is a chronic inflammatory disease, mainly affecting the joints. It typically requires life long-treatment and patients suffer from pain disability and joint damage. The prevalence of RA is about 1%. Disease-modifying antirheumatic drugs (DMARDs) are the cornerstone of early rheumatoid arthritis (RA) treatment with Methotrexate (MTX) typically used as a first line treatment. Methotrexate is a classical Disease Modifying Anti-Rheumatic Drug (csDMARD) contrary to the more recently developed 'biologicals', drugs that are typically monoclonal antibodies or receptor blockers that have a more specific target relevant to the disease process of rheumatoid arthritis. More intensive initial combination therapy with biologicals (like Tocilizumab) has been evaluated in clinical trials showing limited added value with longer follow-up in a treat-to-target (T2T) strategy. Treat-to-target is a treatment strategy where disease activity is frequently monitored using a validated measure, and compared to a prespecified target value (often remission or low disease activity based on a cut-off). When the treatment target is not met, treatment is intensified until the disease target is reached. Such studies report the treatment effect on group level, however, precision medicine requires information on which individuals will respond relevantly better to a more intensive therapy compared to MTX. Precision medicine, sometimes called personalized medicine concerns tailoring treatment to the specific needs and disease characteristics (including e.g. anticipated response to treatment and/or anticipated optimal treatment choice) of an individual patient.

The aim of this study is to identify whether clinically relevant heterogeneity in treatment effect exist (whether an expected difference in treatment effect is sufficiently large to be relevant for decision making regarding treatment choices), and to explore whether individual added value of more intensive therapy can be predicted in early RA patients. This will be done utilizing a "potential-outcomes-framework" which is a framework for identifying the (unobserved) treatment effect/outcome for a specific treatment and a specific patient actually treated with another drug, so that the added value of the specific treatment (compared to the reference treatment) can be obtained (and predicted). As medication always has adverse effects, adding treatment should always also have (sufficient) added value regarding controlling the disease. Also in the early phase of the disease optimal disease control, as soon as possible is warranted, and early knowledge on the added value of a specific treatment option is of high value.