Big Fat FDA Pink Slip (9.19.2025) Save

It's Friday, 09/19/2025. This is the RheumNow podcast. Hi, I'm Doctor. Jack Cush, executive editor of roomnow.com. This week GLP-1s are in the news, acupuncture, what Jack's won't do, and a big fat pink slip from the FDA.

Let's begin with lupus. Always begin with lupus. That's it's like in Dallas. The the news doesn't matter what time of the year it is. They always begin with the, report on football.

Why? Well, because it's a big football town. So we're going to do the same on RheumNow. Always begin with lupus. Everyone loves lupus.

And I like this study because it confirms what we've been hearing, and that is the better biomarker in lupus is a urinary biomarker, and it needs to be available. A study of urinary soluble CD163 levels in two fourteen lupus patients, about half of whom had lupus nephritis, found that CD163 highly correlates with UPCR. Easily distinguishes between active and inactive disease, predicts renal histology and activity with an AUC of 0.96 are you kidding me? And it predicts renal disease flares. And lastly, it allows you to distinguish between those who are complete, partial, and non responders.

This, along with IL-sixteen, you know, and we've heard that from the group at Johns Hopkins, these are the better ways. We need those available now to manage lupus. An important study came out this week that looked at the comparative safety of TNF inhibitors and JAK inhibitors. This is from JAMA Network Open. It was a systematic review and meta analysis, but of head to head trials in all the immune mediated inflammatory diseases, the IMiDs.

And so, I think it was something around like 42 head to head trials, with over 800,000 IMiD patients being enrolled and randomized either to a JAK inhibitor or to a TNF inhibitor. And overall, they found no meaningful differences when it came to serious infections: three point seven nine versus three point zero per one hundred patient years for serious infections. That's what the par is. Malignant neoplasms: one per zero point nine four versus zero point nine four per one hundred patient years. No difference.

MACE events: major adverse cardiovascular events: zero point seven two versus zero point six six on TNF inhibitors or on JAKs. No significant difference. They did find significance in the risk of VTE, venous thromboembolic events. The JAK inhibitors had a higher rate, and that was significant: 0.57 versus 0.52. The hazard ratio was 1.26, a 26% higher risk, and that was significant with confidence intervals being above one.

So again, this is showing you that these drugs are equally safe in spite of many of the concerns that have been expressed in the last few years. Also talking about JAK inhibitors and their potential value is an analysis of patients with either axial spondyloarthritis or psoriatic arthritis. And if you're on a JAK inhibitor or another biologic, does it change your risk of subsequent joint replacement surgery? So, is a commercial claims analysis of eight thousand eight hundred patients with a spondyloarthropathy of one sort or another, and seventeen hundred of them so it's about one in six ultimately underwent joint replacement: the hips or knees. JAK inhibitor use did not reduce the risk of joint replacement.

While there was a trend odds ratio of zero point six seven, it overlapped with one, so it was not significantly different from the comparators. And the comparator here is being on an NSAID. So, being not treated with a sort of just with an NSAID, or being treated aggressively, they changed the risk of joint replacement. Didn't with a JAK inhibitor. However, if you took a TNF inhibitor, or a non TNF biologic, or even a regular DMARD, they did have significantly fewer surgeries with a thirty five percent lower risk that was now significant.

So, it kind of gets close, but doesn't do as well as the other drugs, and there certainly is a lot of patients here on all these different drugs. And yes, the comparison is: will you do better in the future on a biologic or a JAK versus non steroidal? That's a no brainer. But on this particular outcome, does it reduce the risk of joint replacement? Not so much for a jack.

The MMWR this past week updated the CDC recommendations twenty five-twenty six for influenza vaccination. There are many forms, multiple versions of the trivalent inactive vaccine. There's a few versions of the active vaccine, RIV3, and a few sorry, recombinant vaccines, and a few of the live virus vaccines are still out there. The FDA approved FluMist for self administration for those between the ages of two and 49, and if you're under 18, the FDA recommends, and the CDC recommends, that the flu vaccination should be thermal sol free. So, what is the value of flu vaccines?

You know, vaccination's really under the gun here in The United States, with RFK having doubts about that, and appointing committees of knuckleheads who have no experience in this. But here here's the facts: in 2023 and 2024, flu vaccination prevented seven thousand nine hundred deaths. It prevented nine million flu related illnesses, and prevented one hundred and twenty thousand hospitalizations related to flu. And in that same period, there was almost a half million flu related hospitalizations. This is important, you know, and I know some of you may not like the the data on, you know, vaccinations, but these are hard to actually argue with.

And you know, it sort of started in the Covid era for having no good reason, but you know, in Covid twenty '20 there were twenty million infections and four hundred thousand deaths. When vaccination was introduced it lowered the death rate by, you know, ninety percent. It went from one in ten to one in twelve when you compared those vaccinated versus those that were unvaccinated. So again, I'm a big proponent, and this announcement comes because it's the beginning of the flu vaccine season. Now is the time to recommend your patients go to their pharmacy or come to your clinic and get that done.

For me the big news of the week was an announcement from the FDA. The FDA, the July, terminated the Arthritis Advisory Committee. This was a big blow. This is the committee that makes the decisions, the hard decisions, about whether a drug should be approved, or whether it should be approved with provisions. I know this committee intimately, because I was appointed to this committee as a public servant from 2002 to 2006.

Since that time I've been an FDA special government employee, and I've watched FDA activity over the years, and I have a lot of respect for what goes on and the really difficult job that they have to do. These committees make very important decisions about cutting edge decisions and therapies throughout medicine. They're canning this committee, and they cite the fact that it hasn't met since May 2021 what it meant to review the application for avacopan, which was approved based on the committee recommendations. So, because they're not meeting enough, and because there's an effort and expense affixed to maintaining this committee, it is no longer justified according to Doctor. MacKery and his knuckleheads at the FDA.

I think this is a really bad decision. Arthritis drugs, autoimmune, imid related drugs, is a fifty-sixty billion dollar industry. And now, subsequent applications and there's a few that are currently in place You know, the FDA doesn't need to take every drug that's being submitted for use to a committee, but they do when there's a problem. They do when the decisions are difficult. And now the decision is going to be left to some other committee.

Who? The endocrinologist? The drug safety committee? This is like having the Rheumatology Arthritis Advisory Committee advise on the next big cancer advance, or the next big cardiology drug. This is a special kind of stupid.

Write the FDA, complain whenever you can. An interesting report on gout and outcomes comes from Arthritis Care and Research, and it reports on the results of the ESPRIT trial. The ESPRIT trial was published previously in New England Journal, and it was an Australian trial that was really multinational. It was mainly, I think, 35 centers 16 of whom were in Australia and the rest were in The United States and it looked at the value of low dose aspirin in individuals over age 70 and its ability to prevent the primary outcomes three Ds, which was death, dementia, and disability. And in the end the study was prematurely halted after four years because it showed no benefit.

In fact, it showed for death that there were more deaths on aspirin than there were on placebo. But in that trial these elderly people had frequent laboratory tests done, and in this sub analysis of nearly 12,000 elderly people, they showed that serum uric acid levels had no association with all cause mortality, disability free survival, cardiovascular disease, MACE events, cancer mortality, cognitive decline or dementia. And you know, previously it's been said and again, now this is an older population, right? But it's unselected for this particular problem. I think this is a good population to look at.

But previous studies have shown that aggressive treatment of gout will lower mortality, use of allopurinol may lower mortality, allopurinol use even in maybe in cardiovascular patients may lower mortality. This says in an unselected population it does not. And then they do come up with a positive association, a bizarre one at that, in that in females a lower SUA was associated with an increased fracture risk. Don't ask me to explain that, you can explain it to me. Another trial looked at the value of nonsteroidals versus colchicine as prophylaxis in gout patients.

Now this is not a real trial, this is one of those target emulation trials that looks at a large population and looks at an endpoint being cardiovascular events or MACE events in over eighteen thousand individuals. So they had those that were receiving nonsteroidals and those that were receiving colchicine as prophylaxis. They propensity score matched them, nine thousand plus per group. And these people were all starting allopurinol for, the treatment of gout. And then they looked to see what happened, and they found that, patients that were on non steroidals had higher rates of MACE events and cardiovascular death compared to colchicine.

A hazard ratio was fifty six percent higher risk of MACE, and a two and a half fold or two fifty percent increased risk of cardiovascular death with nonsteroidals compared to colchicine. So, maybe the point here is in your elderly population, maybe you don't want to do this, but maybe you don't need nonsteroidals. For instance, I don't use colchicine at all. I mean, I can count on one hand, since colchicine went from being 5¢ a pill to $6 a pill, the number of people who I've written repeated colchicine prescriptions for. Honestly, I don't.

And I've managed all gout, pseudo gout, and flares with nonsteroidals or steroids, and I must say in the first ten years or five, ten years I was using more nonsteroidals and now maybe the last ten years I'm using more steroids as a prevention. And this is again during the early allopurinol initiation phase. But I do the same thing when it comes to how you manage acute gout. So, I don't know if this changes your mind, but this is a fairly well done study and casts, a cloud over the use of nonsteroidals in patients with gout, which means most people not me are going to go back to colchicine. Good luck with that.

The Journal of Rheumatology published and you know this month is, ILD month throughout the world, and on RheumNow we have a gigantic campaign covering all aspects of interstitial lung disease. So we have a few reports this week that I want to review. Journal of Rheumatology reported a nice paper from Jeff Sparks and his colleagues that looked at RA associated ILD or bronchiectasis, and that it was and found that it was associated with an increase in all cause mortality and very specific mortality. So, is a retrospective cohort study of two twenty one patients from the Mass General, Brigham Biobank. One hundred and fifty one had RAILD, seventy had bronchiectasis.

RAILD had a higher mortality, almost a twofold increase in mortality, and infection mortality was more also more common in RAILD, seven percent versus three percent. Doctor. Sparks has a great article on RheumNow this month, part of the ILD campaign, where he says that SARD ILD and infectious risk serious infectious risk it's the elephant in the room that you need to pay attention to. SARD stands for Systemic Autoimmune Rheumatic Disease, and that these people that have ILD, these are incredibly high risk for mortality, and that most of that mortality is driven by infectious risk. He reviews it well, goes over what you need to do to reduce that risk, including the avoidance of steroids, including the use of vaccination, including careful patient selection when it comes to therapy.

Look at that. Another great article from Elena Jorns from PLOS-one was a retrospective study of two hundred patients with IPAF. This is a lot like SARD. SARD is associated systemic autoimmune rheumatic disease with ILD. So that could be scleroderma lupus, Sjogren's, myositis, right?

And they have ILD, and we know that that happens. IPAF is not meeting that criteria, but they have interstitial pneumonitis or pneumonia, but they have autoimmune features, usually, autoantibodies. So in her study from UT Southwestern of two zero one patients followed for almost six years, she found that eighty percent were ANA positive, twenty five percent rheumatoid factor positive, fourteen percent were CCP positive. Ultimately eighty eight percent were treated with either immunosuppressants or anti fibrotics. The bad news is twenty four percent died, seven percent underwent lung transplantation, and in this population comorbidities were common with a Charlson Comorbidity Index of over three.

So, IPAF mortality is worsened by comorbidities. But the other point is, and again, I made this a point this week on the Tuesday night rheumatology webinar with Doctor. And Doctor. Sparks and Doctor. Pope, which you should listen to, it's a really good listen, that, IPAF is to SARD, IPAF ILD is to SARD, just like UCTD is to a defined rheumatic disease, or just like MCTD is to a defined rheumatic disease, but you know I don't like MCTD, I prefer UCTD.

So, it is a forerunner, but this report from Doctor. Says it should be taken seriously. It's not an ANA and a positive consult in an ILD patient that you blow off. These people are at higher risk, and even higher if they have comorbidities. We published, this week an article, on the definitions, acronyms, and abbreviations used throughout this whole lung disease, area.

So, it's a consensus report from the Fleischner Society. Turns out the Fleischner Society is a group of ILD mavens that includes a lot of pulmonologists and radiologists, but no rheumatologists. And I put it up because in my working with the experts on ILD this month they've got tons of abbreviations that we don't know. So here are a few: ILD you know interstitial pneumonia progressive pulmonary fibrosis. You already know about DAH diffuse alveolar hemorrhage.

What about IPF? IPF is the ILD seen by the pulmonologist idiopathic pulmonary fibrosis because they don't got any anything else to refer them to us. That would make them either IPAF or SARD, right? CTD ILD is used to be the term that's often used still in pulmonary world, but the preferred term is now SARD, as mentioned earlier. There's another one called, mentioned IPAF, interstitial pneumonia with autoimmune features, and I guess I'll stop there, because it goes on and on and on.

And so, if you're interested, know the references there for the abbreviations. One last point here is take a look at Dinesh Khanna's article on RheumNow this past week: What you need to know about scleroderma related lung fibrosis. It's like nineteen eighteen points from the expert, Dinesh, where he kind of reviews the multiple guidelines that have been out there, and ULAR just came out with guidelines in 2025 at ULAR, and then the recent ACR guidelines and ATS guidelines, and he kind of puts that into how he practices Be like Dinesh, he knows what he's doing when it comes to this ILD and pulmonary fibrosis. This week we had two reports on acupuncture, one from the Hospital for Special Surgery, showing that if you use acupuncture with surgery or for pain they do well. At HSS they did ear acupuncture applied during hip replacement surgery and showed that those people had less pain and less need for opioids in the weeks that followed.

So, the short term pain benefit. And then another randomized controlled trial of 800 adults adults with chronic low back pain showed that acupuncture was better than usual care when it came to managing pain and pain related disability with at least a six to twelve month benefit. And there was really no benefit to extended acupuncture treatment, so a few treatments or just one treatment might be enough. We should probably be using more acupuncture. Three last reports: the Stop RA was really the big report.

For me the big report was the FDA giving a big pink slip to the Arthritis Advisory Committee, but I think the the major report that we've been waiting for is a STOP RA trial that showed that hydroxychloroquine failed when given to ACMA positive arthralgia patients with preclinical RA, at risk RA. If failed to prevent RA or inflammatory arthritis. The report comes from Kevin Dean and a number of great researchers: a phase two randomized controlled trial of hydroxychloroquine versus placebo in at risk patients who had an elevated CCP and arthralgia. One hundred and forty four patients were treated with either placebo or hydroxychloroquine for twelve months and then followed for twenty four months to see what happened. This study started during Covid, had to bail out early, so they didn't have as many patients they want, but they had enough to do the analysis.

The primary outcome was the development of RA at thirty six months. At twelve months clinical RA developed in thirty four percent on hydroxychloroquine and thirty three percent on placebo. Not significant. When you looked at thirty six months, again thirty three versus thirty nine percent not significant, certainly not any better, and being hydroxychloroquine gave no significant benefit as far as other definitions including inflammatory arthritis, the severity of joint disease, adverse events, etc. Now, can, you know, I had a great question from Art Weinstein about do they look at hydroxychloroquine levels, and maybe that might tell us, well, because you know, we're really disappointed in this.

It's a safe drug, it's an easy drug, it shows so many benefits, why wouldn't it work here? But maybe, I know that Kevin Dean and colleagues intend to do a number of different analyses going forward, and we'll wait for those results. Two last reports about GLP-one. One from ACR Open Rheumatology showing GLP-one works in RA, and the other one from Annals of Internal Medicine, GLP-one might could work in osteoarthritis. So the first report in RA was one hundred and seventy three RA patients who were overweight or obese who took GLP-one drugs and actually took them, versus forty two who were given a prescription but never took the GLP-one.

That was the control group. And there was a significant, like twice the amount of improvement if you were on a GLP-one agonist compared to if you weren't, and that's highly significant. The other important point here is everyone says, well yeah, they all lost weight. Not really. The anti inflammatory event includes lowering of sed rate and CRP and disease activity measures were not related to weight loss, and the difference in weight loss between the groups is only about five or six kilograms.

So this gets to that question of do GLP-1s potentially have an anti inflammatory effect? Now this is a retrospective study, not the design that's going to best answer that, but there are other studies that will answer that in the future. The other one from Adolescent Internal Medicine was a simulation model, kind of like a target emulation trial of knee osteoarthritis. The patients had to have a Womack score of greater than 70 out of 100. This is bad.

Usually to get into an OA pain trial you have greater than 40. And they showed, based on available data, that I can't say these drugs tirzepatide significantly lowered the cost compared to semaglutide, which also was very good, at a yield of 57,000 quality outcomes, and also there was an ICER outcome. But ultimately, RheumWhy gastric bypass was the better outcome, which also led to weight loss, compared to even the two GLP-one agonists, and it was cheaper at 30,000 per QALY. So, I think that tells us a lot about weight loss, I think, a really important thing, and also about the potential value. I think rheumatologists need to advocate for weight loss, I think, and I know you do, but and a strict diet, you know, whether it's a Mediterranean diet or or just weight loss of any kind, is going to help.

But I think for those of you who are the real big I'm going to push diet, you need to be considering these GLP-1s. And for those of you that are really excited about GLP-1s, you need to think about just plain diet, because it's cheaper easier and not everybody can afford or get access to a GLP-one. That's it for this week on the podcast. Check out the links on this week's show notes. I want to remind you ACR twenty twenty five Chicago, Illinois is only six weeks away and we'll be there covering the event.

RheumNow Live is coming up February 2026. You'll be able to register and look at the agenda very soon. It's going to be a great meeting in Dallas. Be there, RheumNow Live. Take care.