Problem to be solved. Rheumatoid arthritis (RA) is one of the most common forms of chronic arthritis in adults. RA affects young women and men. Untreated RA causes disabling pain, deformed joints, and reduced quality of life and functional ability, further leading to loss of work productivity and wages, and short- and long-term disability. Recent discovery of biologics and targeted synthetic disease-modifying anti-rheumatic drugs (tsDMARDs) has revolutionized RA treatment. People with RA, when treated with these drugs, can experience disease remission and enjoy normal lives.
Treatments recommended for RA patients with an incomplete response to methotrexate (MTX-IR, the first-line therapy) include drugs that block the tumor necrosis factor (i.e., TNFi-biologics, such as etanercept, infliximab, adalimumab, golimumab, and certolizumab); tsDMARDs (e.g., tofacitinib, baricitinib, upadacitinib); non-TNFi biologics (e.g., abatacept, rituximab, tocilizumab, sarilumab); or combination traditional DMARDs.
The effectiveness of these biologics and tsDMARDs versus placebo for disease activity and laboratory measures is now understood. However, limited progress, if any, has been made in comparing the drugs’ respective effects on various patient-reported outcomes (PROs), such as sleep, fatigue, treatment satisfaction, function, and work productivity. Therefore, it’s hard for patients to know which medication truly is the best for them. Patients’ medication choices for RA are often driven by considerations such as cost and pharmacy benefits. Many direct head-to-head trials of these medications excluded RA patients with medical comorbidities and compared to only one TNFi-biologic (adalimumab), limiting the generalizability of study findings. For example, an ongoing safety trial of 4,414 RA patients comparing tofacitinib versus TNFi-biologics is focusing on the risk of cancer and cardiovascular events in adults over 50, not efficacy.
A study comparing effectiveness of these RA medication choices on PROs is critically needed to fill these knowledge gaps. Our study will compare whether adding a tsDMARD to MTX is more effective than adding a TNFi-biologic in biologic naïve MTX-IR patients with active RA. We will perform genomic analyses to identify biomarkers predictive of a person’s response to each intervention. We will oversample for individuals younger than 50 years of age. We will exclude traditional DMARD combinations that are infrequently used in clinical practice (about 3 percent of the time) or non-TNFi biologics, a heterogeneous drug group with three different mechanisms of action. TNFi-biologics and tsDMARDs are two relatively homogeneous classes with similar efficacy and adverse event profiles within each drug class.
Outcomes we hope to achieve. Our real-world pragmatic study will enroll people with comorbidities, and a large proportion of people younger than 50 years of age, to assess PROs important to people with RA, which have not been the focus of previous studies. Our study will be the first to compare effectiveness of two treatment strategies, adding TNFi-biologic versus tsDMARD, for improvement in PROs in RA (e.g., physical function, sleep, fatigue, work productivity, treatment satisfaction). Most PROs included in our study have not consistently been captured in efficacy trials comparing these RA treatments in MTX-IR patients. Our study will generate evidence that will fill a critical knowledge gap identified by authoritative sources, and will help people with RA make more informed treatment decisions. Genomic analyses will discover genes associated with treatment response and lead to personalized medicine.
Why this is important to patients. As the first-line therapy, MTX fails to achieve remission in the majority of RA patients. RA patients with active disease despite MTX commonly struggle with the next treatment decision. Ongoing or previous studies have excluded most real-world RA patients and have not compared the effectiveness of these treatment options for PROs in RA. Our study findings of varying effects of medications on PRO domains in RA patients will make personalized treatment options possible.
How patients and stakeholders will make the project successful. Patients, insurers, clinicians, and advocacy leaders were engaged in the development of this study, and helped us identify PROs as a critical knowledge gap and primary study outcome. Patient feedback and pre-piloting helped us select PRO measures that will keep the patient burden of assessments low.
*All proposed projects, including requested budgets and project periods, are approved subject to a programmatic and budget review by PCORI staff and the negotiation of a formal award contract.