Determining MRI Inflammation Targets When Considering a Rheumatoid Arthritis Treat-to-Target Strategy: Results of a Randomized, Placebo-Controlled Trial

The concept of treat-to-target is now well established in the management of rheumatoid arthritis (RA), with clinical targets aimed at low disease activity or remission [1]. Modern imaging, including magnetic resonance imaging (MRI) and ultrasonography, is increasingly used to accurately determine residual inflammation after treatment, as imaging-detected inflammation can predict structural damage progression [2‐6]. However, there is little information on how low inflammatory activity must be on imaging in order to be confident that progression will not occur [5]. Additionally, treating physicians face a challenge when determining to what extent inflammation can be managed with symptomatic treatments alone or when more potent agents, such as biologic disease-modifying antirheumatic drugs (DMARDs), are required.

A previous study suggested levels of synovitis, osteitis and a combined total inflammation score correlated with the risk of structural damage progression independent of clinical disease activity [7]. Validation of these levels would provide physicians with clinically relevant, imaging-detected inflammation targets. Establishing a threshold of inflammatory activity that predicts a lower risk of structural damage progression would help to avoid unnecessary initiation, premature tapering or other changes to treatment, as well as inform the physician on whether a review of treatment was needed. The aim of this post hoc analysis was to examine the outcomes of patients with early RA participating in a large clinical trial, based on their degree of MRI-determined synovitis, osteitis and combined total inflammatory activity, and to validate the aforementioned approach as a predictive trial outcome for non-progression.

This analysis established that lower levels of MRI inflammation below the predefined thresholds [≤ 3 for synovitis, ≤ 3 for osteitis and ≤ 9 (osteitis double-weighted) when combined into a total inflammation score] were associated with a very low risk of MRI-detected, baseline DAS28 (CRP)-adjusted structural damage progression.

MRI is increasingly being used as an outcome measure in RA clinical trials, usually in patients with at least moderate disease activity. Moller-Bisgaard et al. recently reported a randomized clinical trial (IMAGINE-RA) targeting the absence of MRI osteitis versus a clinical treat-to-target approach in patients with RA in clinical remission; no improvement of remission or radiographic progression rates versus the conventional strategy were observed [13]. However, the IMAGINE-RA trial contrasts with the current study with regard to trial design, baseline level of disease and patient populations. For example, in the current study, baseline mean DAS28-CRP score [8] ranged from 5.3 to 5.5 and osteitis scores ranged from 2.5 to 5.1, whereas in IMAGINE-RA, baseline median DAS28-CRP and MRI osteitis scores were 1.9/2.0 and 2.0/2.0 (for both arms, respectively) [13]. Furthermore, the IMAGINE-RA study targeted absence of osteitis, whereas the present study investigates a combined osteitis and synovitis target. Consequently, future trials with treat-to-target endpoints could benefit from including combined MRI thresholds as a primary study outcome measure for joint inflammation, thereby enabling the identification of individuals with a significant burden of inflammatory disease. However, very little is currently known about what level of inflammation may be deemed acceptable (i.e., suggesting that the risk of subsequent damage is low). Subsequently, there will be a need to translate these findings into a readily usable score for routine clinical use. Inflammation score assessments, such as those presented here, may complement standard descriptive or clinical assessments and be used to assess treatment efficacy and to improve the efficacy of clinical studies. Treatment with an effective treat-to-target strategy has been shown to decrease MRI inflammation scores at 6 and 12 months, and has been associated with significant reductions in clinical disease activity and an absence of structural damage progression at 12 months [14].

The work reported here validates inflammatory thresholds defined in earlier research using golimumab trial data: data from the GO-BEFORE trial were used to develop the thresholds, while GO-FORWARD data were used for validation [7]. The current validation was achieved despite differences across the trial populations: patients in the GO-BEFORE trial were MTX-naïve (as in AVERT) [8, 15], whereas those in GO-FORWARD had an inadequate response to MTX [16]. Differences between the golimumab and AVERT trials also included the drug and treatment regimens [8, 15, 16], and patients in AVERT had early RA (persistent symptoms for ≤ 2 years) [8], whereas those in the golimumab trials had a longer-standing disease [15, 16].

In a GO-FORWARD validation analysis, 4.7% of patients with less severe total inflammation (i.e., no greater than the threshold of 9) versus 29.6% of patients with more severe total inflammation (i.e., greater than the threshold of 9) at month 6 had structural damage progression between months 6 and 12 (progression defined as > 0.5; odds ratio: 0.11) [7]. In the current analysis, these figures were 16.0% with less severe versus 32.5% with more severe total inflammation [baseline DAS28 (CRP)-adjusted odds ratio: 0.41]. Overall, progression rates were higher in the current study compared with the golimumab analyses, likely due to the selection of only patients who were seropositive and had highly active disease. To identify an appropriate cut-off for change in MRI, an erosion change of > 0.5, which has been described as a good discriminator of radiography-detected structural progression [12], and SDC, which has been reported to be less variable and enable smaller differences in disease progression to be detected [17], were used in this study. Despite these differences in overall rates of structural damage progression, our analysis supports previous evidence that a low MRI inflammation score is associated with an approximately 80% lower odds of structural damage progression.

In a GO-FORWARD validation analysis of the defined thresholds for synovitis and osteitis, respectively, 7.8% and 9.0% of patients with less severe inflammation (i.e., no greater than the thresholds of 3) at month 6 had structural damage progression by month 12 [7]. In the current analysis, these figures were 11.1% and 18.0%, respectively. The importance of MRI inflammation thresholds regarding subsequent radiographic progression has been documented in previous studies [6, 11, 12, 18, 19].

Strengths of the current analysis include the large trial size and the well-defined study population of MTX-naïve, anti-cyclic citrullinated peptide-positive patients with highly active, early RA. This research also validates earlier work in a distinct patient population treated with a different agent.

Limitations of this analysis, which should be considered when interpreting data, include that, as the study focused on patients with highly active early RA, the findings may not be generalizable to other populations. The work is also a post hoc analysis, with inherent limitations, such as the thresholds described here were not tested in the trial as a pre-specified outcome measure and the relationships between probability of progression and erosion score were from ‘as-observed’ analyses. Radiographic data were not available for this study; however, short-term changes in MRI-detected inflammation have been found to predict long-term changes on subsequent radiography in RA [20]. A limitation of defining low inflammatory thresholds is that older patients and those with osteoarthritis may have detectable inflammation by MRI [21]. However, patients would be very unlikely to have scores above the threshold used in this current study; for example, the median synovitis score reported was 0.5 with an inter-quartile range of 0–2, suggesting 75% of patients from in the general population had scores ≤ 2 [21].

Further research is needed to determine whether these and other thresholds, such as those including tenosynovitis, on MRI are applicable and optimal across different populations of patients with RA and during treatment with DMARDs with different mechanisms of action. Additionally, an investigation into whether achievement of low MRI-detected inflammation is associated with optimization of patient-reported outcomes would be very timely [21, 22] and could form the basis for a logical next study.

In summary, this post hoc analysis indicates that the achievement of target levels of inflammation in patients with early RA is associated with a very low risk of structural damage progression. These post hoc data provide further support for the value of measuring joint inflammation and damage using objective imaging techniques, and indicate that such measures may have the potential to be used as trial endpoints in certain patient populations and to contribute to personalized RA treatment in the future.