Background/Purpose: Most people with rheumatoid arthritis (RA) are prescribed a TNF inhibitor (TNFi) as their first targeted therapy. A blood-based molecular signature response classifier (MSRC) was shown to predict inadequate response to TNFi therapies, before treatment initiation.¹ Identification of likely inadequate responders has the potential to reduce the time spent on trial-and-error approaches for treatment selection. Incorporating this test into clinical workflows could result in improved patient outcomes, reduced patient burden and potentially reduced disease progression.^2,3 In a treat-to-target treatment approach, 3-months post treatment initiation is an important decision point for assessment of response;⁴ therefore, further validation of the MSRC at timepoints earlier than 6 months are warranted

Methods: The MSRC uses data collected at baseline before starting targeted therapy, including gene expression features, laboratory tests (anti-CCP) and clinical metrics (sex, BMI, patient global assessment) to determine if patients have a molecular signature predictive of inadequate response to TNFi. The MSRC was used to evaluate RA patients (N=96) from the CERTAIN study⁵ who were initiating a TNFi as their first targeted therapy. None of these patients were included in previous MSRC validation studies, and only baseline and 3-month follow-up visit data were available. MSRC prediction of inadequate response were compared to treatment response, ACR50, reported at 3 months. Odds ratios and area under the receiver operating characteristic curve (AUC) were used to evaluate the ability of the MSRC test to predict inadequate response to TNFi therapy at 3 months.

Results: Of the 96 RA patients described in Table 1, 51.0% (49/96) had a molecular signature of non-response. An ACR50 response at 3 months to a TNFi therapy was observed in 20.8% (20/96) of patients. Patients were stratified according to detection of a molecular signature of non-response to TNFi therapy with an AUC of 0.63. Patients with a molecular signature of non-response were 3 times less likely to satisfy the ACR50 response criterium at 3 months compared to patients lacking the molecular signature (odds ratio 3.0, 95% confidence interval 1.1-8.8).

Conclusion: The MSRC identified RA patients who did not fulfill the ACR50 response criteria to TNFi therapies by 3 months post-treatment initiation. Minimal response to treatment at 3 months is indicative of poor treatment response targets at later timepoints.^6,7 Thus, MSRC test results received prior to treatment could support targeted therapy treatment selection in treat-to-target management strategies.

References:

1. Mellors T et al. Network and Systems Medicine 2020

2. van Nies JA et al. Ann Rheum Dis 2014

3. Schipper LG et al. Arthritis Res Ther 2010

4. Aletaha D et al. Ann Rheum Dis 2016

5. Pappas DA et al.. BMC Musculoskelet Disord 2014

6. Aletaha D. J Autoimmun 2020;

7. Norvang V et al. RMD Open 2018

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-molecular-signature-response-classifier-predicts-the-likelihood-of-non-response-to-tnf-inhibitor-therapies-in-ra-at-3-months/