Vibeke Strand, MD, MACR, FACP

Advancing the State of Precision Medicine in Rheumatoid Arthritis

01:29 Precision Medicine in Rheumatoid Arthritis (RA)

03:34 Biomarkers and Diagnostic Tools in RA

07:08 Science Behind Molecular Signature Response Classifier (MSRC) Test

08:30 Accelerate Information of Molecular Signatures (AIMS) Study

10:33 Experience with MSRC Test in Clinical Practice

12:46 Heterogeneity of RA and Development of Other Biomarkers in RA

14:49 MSRC Test Coverage by Medicare and Future of Precision Medicine in RA

17:54 Safe Step Act in RA Management and Success in Utilization of Precision Medicine

20:48 Final Thoughts and Recap of Discussion

Videos

Expert rheumatologists discuss precision medicine in rheumatoid arthritis. In particular, they discuss available data and the value of various tools in guiding treatment selection in routine clinical practice.

Advancing the State of Precision Medicine In Rheumatoid Arthritis

To watch the video series component of this episode, click here.

Podcasts

If you find you’ve got a patient who’s a nonresponder to a TNF [tumor necrosis factor inhibitor], it can be difficult to prescribe another therapy. A good example of this is the JAK inhibitors. where our US FDA has required that a patient fail a TNF before they receive a JAK inhibitor. That’s not a great idea. If you know the patient is unlikely to respond to a TNF inhibitor, you’re then, shall we say, forcing them to spend 3 or 6 months with an incomplete clinical response before they can move to some other therapy. As I said to you before, there are certain situations where JAK inhibitors are much preferable. But we also have abatacept, which works well in early disease, especially if they’re CCP [cyclic citrullinated peptide] positive. And we have IL-6 [interleukin-6] inhibitors, and we also have rituximab. So we have these other alternatives, and unfortunately, none of them we are able to use early in the course of RA [rheumatoid arthritis] after, say, methotrexate failure, or even with methotrexate as moving on, unless there’s some way to negotiate through the insurance companies and the formularies.

When you’re talking about treating a patient with moderate vs high disease activity, we’re going to use the same choices of therapy that we have. All classes of these therapies are effective, and we know that. And unfortunately, we don’t know why to argue for one therapy vs another. Again, I might think for a patient with early disease who is CCP positive, whether they’re moderate or high, I might choose abatacept. But I have every other reason to think about an IL-6 inhibitor, rituximab, or a TNF inhibitor, or a JAK inhibitor. The only reason you would treat a patient with moderate disease activity differently from one with high disease activity is whether you use concomitant therapy. With high disease activity, you may continue the background methotrexate if the patient can tolerate it. You may also add a short course of prednisone to try to encourage onset of response. You may add a combination therapy, although in general, other than using methotrexate with a biologic or a targeted synthetic, we don’t use others. Although sometimes physicians will use hydroxychloroquine. The biggest difference is simply being able to treat the patient, and treat them efficiently and see them more frequently, if they have high disease activity in hopes of being able to control their therapy.

We should be optimistic that other classes of therapies will be developed because we’re treating 40, 50, 60 years of disease. It’s simply a matter of time until patients have need of another therapy. That’s an important point.

We have many effective therapies now, which is nice, because I remember when we only had methotrexate. There are many still in development, even if I haven’t told you that I’m particularly excited about some of them because they’re not in late development. And the fact that we already have choices for oral as well as self-injected therapies. That’s a big advantage. Patient selection is crucial, and following patients closely and monitoring them is obviously crucial if you can get them into low disease activity or remission in a shorter period of time, such as 3 or 6 months. But selection of the agent for the patient, as crucial as it is, we have so little to guide us on that, other than essentially clinical practice and long-term acumen from lessons learned. But I can’t tell you now, even after 40 years, what patient should receive what therapy, which is unfortunate.

Vibeke Strand, MD, MACR, FACP, shares the advantages and limitations of the AIMS and comparative cohort studies in the treatment of RA.

Improving Management of RA

The AIMS study, which is named Accelerate Information of Molecular Signatures, was to essentially develop a clinical database of longitudinal data from patients with RA [rheumatoid arthritis] treated by providers in real-world settings. In other words, in clinical practice, with the idea of looking at what happens when the MSRC [molecular signature response classifier] test is utilized or not utilized. It includes more than 70 private and academic rheumatology practices across the United States. The major response was looking at ACR50 [American College of Rheumatology criteria for 50% or more improvement] at 24 weeks.

They were looking at therapy, whether it was selected according to the MSRC test or not, and they had MSRC results for 73.5%, or 277 of 377 patients tested. Interestingly enough, there were those who didn’t follow the MSRC results, and about 60% of that was because they couldn’t due to the formulary restrictions or having insurance that would not cover an alternate mechanism of action therapy. When you look at the data, the primary data are at 24 weeks, ACR50 responses were much higher in those patients who were prescribed a therapy that was in alignment with their MSRC results. Overall, that was about 40%. Those who had a signature of nonresponse significantly improved if they didn’t get a TNF [tumor necrosis factor] inhibitor. And if they didn’t get a TNF inhibitor, their ACR50s were 34.8% vs those who were prescribed a TNF inhibitor, which was only 10.3%, which was a 

value of .05. Again, showing the statistical significance of testing this prospectively. We also noticed significant changes with the CDAI [Clinical Disease Activity Index], ACR20, and ACR70 responses, and for responses earlier, at 12 weeks.

Now, the predicted TNF nonresponders who were treated with an alternative mechanism of action hadabout a 1.8-fold greater improvement in CDAI scores than those who received a TNF inhibitor. Those numbers at 12 weeks were 12.2% vs 8%, 

 value nonsignificant. But at 24 weeks, it was 14.2% vs 7.8%, which was a 

 value of .009. In other words, in predicted TNF nonresponders with high disease activity at baseline, using this test corresponds to a 43% relative improvement in achieving a lower CDAI disease activity level. Thus, it makes sense to follow the prediction of nonresponse to a TNF inhibitor and prescribe an alternative mechanism of action. This goes against formulary and insurance restrictions in at least some settings.

This second study was a comparison of 627 MSRC-tested patients from the AIMS study who were now compared to an external control arm from US electronic health records, which included 2721 patients between August of 2020 and August of 2022 who were starting a new biologic or targeted synthetic DMARD [disease-modifying antirheumatic drug] or a TNF. The idea was to compare the AIMS data with a broader cohort of patients starting therapy. What was interesting is that in the MSRC-tested cohort, the 627 patients, 58% had a signature for nonresponse to TNF inhibitors, and 70% received treatment according to their MSRC results.

Interestingly, in the TNF-treated patients, the MSRC had an 88% positive predictive value and 54% sensitivity. Those MSRC-guided treatment patients were significantly—

 value less than .0001—more likely to respond to a biologic targeted synthetic than those treated according to standard of care, based on what we don’t know about how to treat. The difference was that the CDAI low disease activity and remission outcome was achieved in 36% vs 21.9%; that was an odds ratio of 2.1. And essentially, CDAI remission, an even more stringent outcome, was 10.4% vs 3.6%, and that was an odds ratio of 3.14. Finally, if it was just CDAI minimum improvement difference, it was 49.5% vs 32.8%. Again, an odds ratio of about 2.

These data clearly show again that the MSRC is proven to be predictive and that there is a significant difference between use of MSRC-guided therapy vs use of whatever therapy is chosen. What this means is that MSRC-aligned treatments are clearly better in terms of responses than what we obtain in regular clinical practice. You may remember that I told you the best published responses to TNF inhibitors outside of clinical trials is only about 30% to 40%.

An expert rheumatologist discusses the Accelerate Information of Molecular Signatures (AIMS) study and the comparative cohort study of the MSRC test.

Vibeke Strand, MD, MACR, FACP

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