Vibeke Strand, MD, MACR, FACP

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.

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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.

AIMS Study and Comparative Cohort Study of the MSRC Test in RA

I don’t think we have a lot of tools to tell us how to treat and what therapy. We know there’s the R4RA trial where synovial biopsies were performed, and RNA [ribonucleic acid] sequence-based identification showed that patients with low or absent B-cell lineage gene expression signature in their synovial tissue were significantly correlated with a better response with tocilizumab than rituximab. That makes a lot of sense, but we don’t have any more data from the R4RA for any other therapies. And there’s always the issue about synovial biopsy and obtaining those to get data. Unfortunately, synovial biopsies are something that we perform once. Most patients, once they’ve had one, aren’t willing to have a second one. So you aren’t able to follow those findings serially or to see what the effect is after 1 therapy. The only thing we have right now is the Scipher [Medicine] test, the MSRC [molecular signature response classifier]. It’s new and I don’t know that it’s widely used yet, but hopefully, it will be recognized as something to start with.

The MSRC is a molecular signature response classifier, and it is used for nonresponse to TNF inhibitors. In other words, who’s a patient who will not have a good result with a TNF inhibitor? It’s a tool that utilizes gene expression profiling, and that came from synovial biopsies. Again, it’s to predict the response of patients with RA [rheumatoid arthritis]. This therapy includes the gene expression data as well as microwave gene expression data, RNA sequencing, biologic network analyses, and machine learning. Essentially putting all this together in large patient cohorts has been able to identify a set of genes that are differentially expressed between those who respond to a TNF and the nonresponders, which are identified now by this test. It includes things like the genes, as I mentioned, also anti-CCP [cyclic citrullinated peptide] serologic status, age, sex, and BMI [body mass index]. This is made into a predictive algorithm. It’s numerically valued from 1 to 25. Those patients who have scores above 10.6 are considered to be nonresponders to TNF inhibitors. Overall, it’s a 23-feature molecular signature. In other words, it’s measuring 23 biomarkers that especially consider the pathways, both upstream and downstream, from what TNF does in rheumatoid arthritis.

Vibeke Strand, MD, MACR, FACP, reviews the tools available to clinicians to improve treatment selection in RA, focusing on the molecular signature response classifier test.

Tools for Improving Treatment Selection in RA

The TNF [tumor necrosis factor] inhibitors are a fantastic class of therapy in rheumatoid arthritis [RA], and our first effective biologic therapy. We now have 5 of them, which is a nice thing. However, usually only 1 or 2 are included in the formulary. Although they behave similarly, there may be some reason that a certain patient or physician would like to use one vs another. That may be a bit problematic, but that’s not a major problem. Using the TNF inhibitors is widespread. We have 23 years of data on this class of therapy. They’re quite safe, and they’re easy to use if you don’t mind subQ [subcutaneous] injections either every week or every 2 weeks. Those are great advantages. Where it becomes maybe less of an advantage is say for a patient with early RA who’s a student at university, or even at school. They may not necessarily want to be burdened with having to give themselves injections, and having to find a place to refrigerate the medication, and take care of it and all of that. That is a burden for some people. Also, there are a lot of patients who may be business people or travel extensively. It’s no fun to travel with these subcutaneous injections. They have to be kept cold, so you have to have a special way of taking them, and all the issues about needles, everything else and TSA [Transportation Security Administration] screening.

We’ve seen more or less that it’s 30% to 40% of patients who respond to a TNF. If they don’t respond at all to the first TNF, it’s certainly worth trying a second TNF. But in general, if they’ve failed 1 TNF, we think you do better by switching class. That doesn’t give us much of a choice of the 5 different TNF inhibitors when we want to use them. How many fail after they’ve been taking it? We have patients who’ve been taking TNF inhibitors for 10 years and more, and do really well. But at some point, they may fail the therapy, and then we have to switch. It’s hard to predict how well anyone will respond to a TNF inhibitor, or for how long.

There are a lot of long-term consequences of staying on partially effective RA treatment. Unfortunately, as we look across data and patient series and registry data, we see that a large majority of patients with RA are on only partially effective RA treatment. Now part of that was that we didn’t have as many choices in therapy, but that’s no longer true. What’s problematic is that people don’t follow patients as closely or as stringently for response. Yes, there are the ACR [American College of Rheumatology] and EULAR [European League Against Rheumatism] guidelines, but I don’t know how many practicing clinical rheumatologists are paying attention to definitions of remission. And thinking that when somebody is in low disease activity, that’s sufficient. That’s where we get the disadvantages and the challenges of partially effective RA treatment.

Of course, what happens is that the disease progresses, and when the disease progresses, we get more structural damage. We get more loss of physical function, and patients have worsened health-related quality of life, physically, mentally, emotionally, and very much socially. That means also that they may have difficulty working, and they may also have issues with being socially active, doing things with their family and friends. It’s unfortunate because we should be able to get most patients into at least low disease activity, and preferably even remission. I don’t think we believe there is such a thing as drug-free remission, but there is such a thing as remission. And many patients who have been treated more recently, having been diagnosed more recently, are more likely to go into remission.

Dr Vibeke Strand highlights the use of tumor necrosis factor inhibitors in the treatment of RA.

Vibeke Strand, MD, MACR, FACP

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