Cancer Survival with TNF Inhibitors (3.28.2025) Save

Hi. I'm Jack Cush with rheumnow.com. It is the 03/28/2025, and this is your podcast for this week. Let me begin with a request. I would really appreciate if you would give us a rank wherever you listen to this podcast.

A thumbs up would go a long way. I know you enjoy it. I get lots of good feedback from you. I'd also like to know how we could possibly improve it. So your comments, your notes, your request would be much appreciated.

This week, let's get into Behcet's. We don't talk a lot about Behcet's, but, there was a review, interestingly done by a bunch of underwriters, not like Behcet's scientists, and they were looking at what to think about when it came to mortality statistics with Behcet's patients. So they looked at the Korean national database, and their insurance claims, and looking at a fairly large population, they found that the overall mortality for Behcet's was significantly increased with an odds ratio of one point two eight or a twenty percent increase compared to age matched individuals, and that that increased in mortality was actually highest in the first year. And I find it surprising because I don't see really bad serious bichettes in my Dallas population, in my training and years of practice. Again, the, our mortality risk is even higher than one point two eight, it's two point six six in that first year.

Causes of death were cancer, cardiovascular, as you might expect, GI, and that would be, viscous rupture, respiratory and infection. And again, the younger the patient, the higher the mortality risk, meaning the younger they were at onset. We often talk about cancer. You're often worried about cancer. What do I do with my cancer patients when they have RA?

And they may or may not want to take the therapies I use and you're afraid to write for them? I'm not. And you know the rule we've talked about before, you've got a solid tumor, the ACR guidelines say treat the patient as if they didn't have a solid tumor or any tumor, it doesn't matter. Okay, and this is a study coming out of MD Anderson, a great, center for cancer care in Texas, and their study of almost two thousand patients who had rheumatoid arthritis and either prostate cancer, lung cancer, or colorectal cancer. They showed that using a TNF inhibitor in the first three years after the diagnosis of cancer had no effect on overall and or cancer survival.

They compared those who were on TNF versus those who are on conventional DMRs. If anything, they saw a non significant lowering of cancer risks. The numbers were, something like hazard ratio for colon cancer of zero point seven two, but the confidence intervals were 0.43 to 1.21. Same thing for lung 0.7 o, same thing for prostate zero point eight o. Again, a trend downwards rather than increase.

What they found that did increase your risk of cancer were these patients, who were on these drugs, but were also on steroids. Steroids imparted a lower survival statistic as steroids often do, and steroids being itself a risk factor, but also a surrogate marker for patients with more serious disease. There was another study coming out of the Kurama cohort studies. This is a Japanese cohort study. We talked about that a few weeks ago, but here's another one where they looked at the ability to use machine learning to predict those who had seronegative RA arthralgia who might progress to undifferentiated arthritis.

Now, know, if they're seropositive and they have undifferentiated arthralgia, the risk is thirty percent. If it's seronegative, it's way less. Well, in their studies, they developed a model to predict those who had progressed from seronegative undifferentiated disease to not seronegative, but to RA, being diagnosed as RA meeting criteria. So in their, development cohort, two ten patients were seronegative, twenty seven percent progressed to develop RA, so much for the influence of seropositivity. In their final model, they actually achieved a sensitivity of eighty one percent, with an AUC of 0.924.

They took that model and applied it to another dataset, the answer cohort, and showed in that one hundred and forty patient cohorts, thirty two percent developed RA eventually, and it had similar performance, but not quite as good. AUC of 0.77, sensitivity went down from 81 to 78%. I think that's pretty good. They found that MMP-three was part of that model that could help predict progression in these very early patients. I often will throw up what looks like marketing data from time to time just to give you a feel for what the marketers are thinking.

This one I put up this week said the value of the rheumatoid arthritis market worldwide in 2021 was valued at almost $23,000,000,000 worldwide, and is expected to grow to 2020, two thousand and thirty five years from now to a $33,000,000,000 market. Now these numbers do change depending on who's doing the analyses. These are usually based on either five or seven large worldwide markets, so it doesn't include Lithuania, but does include Japan, and South American countries, etc. So again, the market's gonna grow. Number of patients gonna grow slowly, but not as much as the number of new available drugs and spending on these drugs, and that's something to consider.

An interesting animal study, mice study showing that JAK inhibition may affect seizures and actually help prevent seizures. So a mice model of status epilepticus showed that when you initiated the JAK inhibitor tofacitinib, really no effect on what was going on during the initiation period. However, on a second round where there was going be a second wave of status epilepticus, those that were pretreated with tofacitinib had suppression of seizures, suppression of induction of seizures, improvement in histopathology that was related to seizures in mice brain models, and that the suppressive effect of the JAK inhibitor lasted for weeks or months after the drug was stopped. I mean, again, don't know that I would have ever suspected that. We haven't had a lot of data on neurologic benefits of JAK inhibition, but I'm not surprised to see more research going on in this area.

A Scandinavian study done by the Swedes, looked at five Scandinavian cohorts, almost 6,900 patients, and looked at the specificity of ACPA to see if it had something to do with or was related to the presence of the shared epitope. Normally, they found that ACPA usually, targets glycine citrulline motifs. But here they found that non glycine citrulline motifs targeted or bound by ACPA antibodies was strongly associated with shared epitopes. The usual glycine citrulline motifs was more associated with, smoking and IgA ACPAs. This is in arthritis and rheumatology.

Tori Klein and others who've done great work in this area said some gives us some insight into ACPA, activity being somewhat T cell dependent. But the true significance of ACPA binding to especially nonglycine citrulline, protein structures, remains to be seen. I think this is interesting because this is how discovery, I think, occurs. You find something, it becomes a head scratcher, but it becomes seed information for subsequent research that could tell us more about and we know ACT was vitally important to a homogenized version of what we might call RA, and RA might be either four disorders or 24 disorders based on, number of factors. But I think ACPA, the way we commercially test for it is one unifying homogeneous set of people that we can certainly study.

You may have seen, a video report, I saw this on Twitter and I retweeted it. It was an interview with Swamy Ventura Pali. As you know, Swamy has been very involved with the ACR and is in practice out there in California. I work with Swamy and Jeff Curtis and a number of other great researchers in developing an ACR, REF, RF sponsored project to develop a tool that patients could use for self assessment. And that this was going to be a tool that was going be vitally important for telehealth evaluations.

Of course, this was funded around the time of the pandemic. It was very important. This was developed by the arthritis power people and the, creaky joints folks, and it was tested in practice and shown to have high utility. It's an app, it's on your phone that your patients can use and using the app and going through, they show the patients how to do a self joint exam, how to assess your MCPs and your wrist. And it does a very valid, joint exam as compared to that done by the rheumatologist.

Many of you who don't like telehealth have said, well, I don't know how to examine people or, you know, by video. Of course, I've told you I have a video out there that I think is very valid and I've used in telehealth evaluations. Hence, I'm really strong and, a big supporter of telehealth for rheumatology practices. Many of you don't like relying on that tool. This is another way of doing it and having a reliable validated tool that patients can do their own exams.

I endorse this, of course I would, I was part of the project. And believe me, would could ask Jeff Curtis and Swamy, and the other team, I wasn't always the easiest guy in the project. I would have lots and lots of questions and lots and lots of doubts, and they definitely won me over with their data and how they went about developing this tool. Interesting data coming out of the belimumab clinical trials, know about its efficacy, it's FDA approved. How you use it is up to you.

We'll talk about that, I guess, in the future. But I like this post hoc analysis of five phase three balloon mam trials that look mainly at skin outcomes. So this is BLIS one, two, BLIS nine, seven, eight, whatever, and a whole bunch of others, where they look specifically at the BIOLAG and the SLEETi2K, but the skin version of those, the so called mucocutaneous versions of BIOLAG, mucocutaneous versions of SLEETi2K, showing that Bolivolix was very successful in controlling skin outcomes, shows odds ratios with the MC Bilag of 1.29, with the MC S SLETEI of 1.37. These are very significant. This worked in patients who had very active disease with SLEDI two ks scores greater than 10 or patients who are double stranded DNA positive.

They also showed, as you might expect, belimumab was effective in all these models at preventing skin flares, not just treating skin outcomes. So I like that. I mean, it answers the question I initially asked a lot when blimumab was first approved. It was approved for use in lupus, and then I wanted to know exactly who do I use this in? Well, we know blunavab is actually FDA approved now for glomerulonephritis.

We have this data, post hoc data looking at SCID. A study of fifty five inflammatory myositis patients looked at nail fold capillary studies its association with either cytokine levels, myositis specific autoantibodies and interferon gene, profiling. So they found that the MDA-five positive patients had significantly more dilated capillaries, giant and abnormal morphology capillaries and micro hemorrhages compared to, patients with the antisynthetase syndrome. Micro hemorrhages and dilated capillaries were associated with a number of different cytokines, m x one, I f I 27, I p o 10, rantes, and Gro alpha, and that they did find that giant capillaries were associated with, again, I f I 27, SDIF, SDF one alpha, and also interferon signaling. So I think, again, it's one thing to do a nail fold capillary evaluations in IIM patients, I do it, but it's good to know that these have true biologic correlates and that could be helpful in choosing therapy for people going forward.

J and J announced this week that the FDA approved their investigational drug nipocalimab. We talked about that in the past that it's being fast tracked for, its study in adult patients with moderate to severe Sjogren's syndrome. That is the FcRn, neonatal receptor antibody that, has been at least in clinical trials and now it's going into phase three. You may have seen the report this week on worse outcomes in B27 JIA patients. I saw that I thought, I don't know, is that important or not?

Well, again, this was I think a large, cohort. I believe it was a Swedish cohort, five 10 patients, four thirty four they had data, that they could use for the analysis and they showed that I think it was around twenty two percent of the patients had B27. As you might imagine, they were largely male and older, and they also had, more of specific joints associated with that ERA or late onset spondyloarthritis group, sacroiliac hip and subtalar joints, they also had more enthesitis, more uveitis. But the more important thing is that if you had JIA, any kind of JIA, and you were B27 positive, you had a 2.6 higher risk of when getting out of being a kid or adolescent and continuing to have disease activity as an adult with synovitis and enthesitis. And I think that that really is important and it begs the question about whether or not we should be doing B27 testing in all kids with JIA, not just the older ones or not just the ones who have hip or enthesitis or whatever.

So I think that's a, instructive, report that was worth, putting out there. Another useful review article this week came from Adult Rheumatic Disease. Ian MacInnis and colleagues did an interesting review basically saying, we know about obesity and rheumatic disease patients. It's a big problem. Is it a time we'd start doing something about it?

Again, they note a few things worth mentioning. Seventy percent of rheumatic patients are either overweight or obese. We have, paid attention to mortality by using more effective anti inflammatory immunosuppressive therapies and shown good results. We've paid attention to smoking and, significantly trying to reduce risk by, interventions with smoking. Are we doing the same with weight reduction and managing obesity?

It's a big problem. Or what are you doing about it? Again, obesity runs with a bad pack of the metabolic syndrome disorders, type two diabetes, cardiovascular disease, etc. But is problematic in all inflammatory arthropathies, osteoarthritis, more mental health, more infections, more liver disease, etc. And we do know from other many studies, not just in psoriatic arthritis, but many studies that weight loss can have a significant disease modifying effect in our patients.

Lowering the risk lowering weight and taking patients out of obese categories into overweight, out of overweight into normal BMI is gonna be less traumatic disease, less disease severity, improved DMARC responses, less adverse effects, maybe less infections, improved ADL function, and reduced comorbidities. I think it's a really nice article that makes a strong statement about rheumatologists needing to step up and manage obesity. The last report from yesterday was from the British Journal of Anesthesia. I know you don't get that. I don't either, but I found this report of repetitive transcranial magnetic stimulation in fibromyalgia and its efficacy.

Let me say it again. Repetitive transcranial magnetic stimulation in fibromyalgia, it sounds incredibly goofy, but it's and it's in a remote journal. But a 101 women, I don't know why they only studied women. I couldn't figure that out. 48 years of age, and they had treatment refractory fibromyalgia.

Maybe it was women because there are more women with fibromyalgia. So and they were split. You know, fifty two got the active treatment with transcranial magnetic stimulation or sham stimulation. They started out with daily stimulation for, I don't know, I wanna say it's two weeks, and then for another week, they did it once weekly and then after that it was twice week, every two weeks. And they found that at week eight, significant improvement in pain reduction, forty percent pain reduction with active treatment versus eighteen percent with sham, and that was significant week eight.

So if you looked at the pain responses from day one, day two, they're kind of running together, But then after like day eight, you get separation on pain responses between those that were getting magnetic stimulation and those that were getting sham. And that was there till week eight. After week eight, when they went to, to week 16, when it was every two weeks, you lost the efficacy on pain scores, but the fibromyalgia impact questionnaire scores were still significant at week 16. So I don't know, I like any positive study that can help us control pain. And it controlled a lot of parameters that are unique and important to patients with fibromyalgia.

It did not affect depression. Okay? It did improve anxiety, which I don't understand. But I don't know, I get anxiety sitting under a big magnet on top of my head, you know, daily and wondering what's that doing to me. But anyway, this is encouraging data and I would encourage them to do more studies with larger amounts and again, really working on the design of the trial as being a key factor on the applicability of this data.

I want to remind you if you've got a great case that you'd like for me to discuss, it's on go to the website, click on the bottom left hand corner, click on ask Cush anything. I'll play your recorded message to me. Don't tell me your life history. Give me a one minute synopsis of the case and the question, and we'll discuss it here on the podcast. Those of you who were, participants in RheumNow Live twenty twenty five about, not quite six weeks ago should be receiving your, RoomNow live review questions.

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