The Effect of Guided Care With Vectra Compared to Treatment as Usual in Patients With Rheumatoid Arthritis

Disease activity in RA can be assessed by physical examination, patient-reported outcomes (PROs) or laboratory tests. Joints counts and PROs are partly or entirely subjective. Their ability to support clinical assessment is limited in certain settings, including for RA patients with common comorbidities, such fibromyalgia, obesity, or depression, or with clinically uncertain inflammatory burden. It can be difficult to assess the origin of ongoing pain in such patients using clinical assessment alone. The two blood tests routinely used to assess RA disease activity, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), are objective but are in the normal range in more than half of RA patients with active disease, which reduces their negative predictive value and greatly limits their utility. These clinical and laboratory measures are variously combined in composite scores of RA disease activity, such as the 28-joint count Disease Activity Score (DAS28) or the Clinical Disease Activity Index (CDAI) which are not widely used in the US outside of clinical trials because complete, formal joint counts are time-consuming and composite scores pose logistic challenges in a busy clinic setting.

Radiographic progression (RP) is a validated endpoint accepted by the FDA for clinical trials that reflects RA-related damage to joints. It is associated with long-term disability. Optimal care requires that the risk of progression be reduced. Quantitative scoring of RP is performed only for clinical trials and is not used for assessing RP risk in clinical practice. Rheumatologists are generally not trained to score radiographs and they are very time-consuming to score, typically taking 20 or more minutes per patient for a skilled reader. However, they are a valuable scientific endpoint in that they serve as a valid proxy for long term damage and associated RA-related disability. Conventional clinical and laboratory-based measures of RA disease activity are weak predictors of RP, including among patients in clinical remission, where progression can still occur. Thus, an objective, convenient measure that reflects pathologically meaningful disease activity and predicts risk for progression is needed for optimal management of RA.

The multi-biomarker disease activity (MBDA) test, Vectra®, is an objective tool that combines serum concentrations of 12 biomarkers in a validated algorithm to produce a score on a scale of 1 to 100. The MBDA test was subsequently adjusted to account for the effects of age, sex, and leptin (a surrogate for adiposity) in patients with rheumatoid arthritis (RA). The Vectra score has been shown to be the strongest predictor of risk for RP, compared with conventional disease activity measures, including DAS28-CRP, CRP and the swollen joint count. In multivariate analyses, it was the only disease activity measure to independently predict RP. High Vectra scores (>44) are associated with greatest risk for progression and low and moderate scores with very low risk. Across multiple studies, Vectra has a negative predictive value for progression of 93-97%, and in a meta-analysis, the relative risk for progression with a high Vectra score (5.1) is substantially greater than with a high DAS28-CRP (1.4) or high CRP (1.6). The predictive value of Vectra exists even when the Vectra score and clinical measures are discordant, which means that patients with high DAS28-CRP have little risk for RP when Vectra score is low and, conversely, patients with low DAS28-CRP have high risk for RP when Vectra score is high.

Thus, reducing high Vectra scores should be a primary goal of therapy, regardless of the level of clinical disease activity, and using Vectra scores to guide therapy should be an effective way to prevent radiographic progression. A recent prospective study of daily and diurnal variation in Vectra score established that the minimally important difference (MID) in Vectra score - i.e., the magnitude of change in Vectra score that is needed to be confident that it reflects real biologic change and is not due only to random variation - is greater than or equal to 8 Vectra units. Accordingly, a threshold of 8 can be used in guidances for using Vectra to evaluate treatment response.

The primary objective is to compare the clinical response from baseline to 12 months among patients with RA receiving Vectra-Guided care versus those receiving usual care.

The secondary objectives of this study are to:

• Evaluate the rate of radiographic progression from baseline to year 1 among patients with RA whose care is guided by Vectra relative to those receiving usual care.

• Evaluate changes in Vectra score from baseline to 6 months and baseline to year 1 among patients with RA whose care is guided by Vectra DA relative to those receiving usual care.

• Evaluate clinical response from baseline to 1 year among patients with RA receiving Vectra-guided care relative to those receiving usual care.