World Changers (3.14.2025) Save

It's the March 14, almost the ides of March, and this is the RheumNow podcast. Hi. I'm doctor Jack Cush, executive editor of roomnow.com. This week, we go around the world, an Afro Caribbean study, a Dan Bio Danish study. We got global studies.

We got the global wacky wide world of rheumatology overview. So let's begin with a global study, a global burden of disease study. You know, Lancet's been doing a series of articles about global burden of disease, and they featured arthritis a few times. In the most recent issue, they talk about the global burden of disease with osteoarthritis, especially in postmenopausal women, and note that it is increasing. So from what looks like a thirty year period from 1990 to 2021, a 1.3 fold increase in OA incidence, prevalence, and disability adjusted years of life, in women that are postmenopausal.

The greatest burden to society is knee OA, and in their listing a lot of other forms, hip OA was actually the least, amongst the burdens. But I find that interesting, because if you look at data on the number of knee and hip replacements, knees outdo hips significantly in most countries, but hips aren't far behind. So, it's more than just surgery. The one thing you might expect that they found their study that was at BMI was the single greatest risk for burden of OA. Interesting.

A chronic pain study, a meta analysis of almost 400 patients, almost 400,000 Sorry, almost 400 studies, almost 400,000 patients found that in all these studies in patients with chronic pain, that about forty percent had significant depression and or anxiety. Depression anxiety was more common in women and in younger people and patients with nocoplastic pain. For rheumatologic disorders, it was highest, being depression was highest in fibromyalgia fifty four percent in this meta analysis. And somewhat lower, about half that rate twenty seven percent, twenty eight percent in patients with OA and RA. Again, I've pointed this out in the past I'm using this to underscore the point: it's a big issue.

Ask about it, measure it, do a PHQ-nine survey, PHQ-two or three question survey that you can put into your survey to know at least when it's on the table and when it could be complicating the management of your patients. Sobi, the makers of Anakinra, are also makers of Emipalumab. We talked about that before. It's marketed as Gamafant. It's FDA approved for use in hemophagocytic syndrome.

They announced that they submitted their supplemental biologic license application for emapalumab for use in adults and kids with either macrophage activation syndrome or HLH in those with Still's disease. Again, we've reviewed the data on that before. The indication is Still's disease with MAS or HLH who've had an inadequate response to steroids or those who had recurrent MAS events. This is in front of the FDA. We'll see if they'll make a decision based on a limited data set.

I think that the last data set we had in there was about fifty patients. Speaking of Still's disease, I put up the results of a observational 58 patient cohort study. It was novel in that it was from The Caribbean. So, are patients of Afro Caribbean descent who have Still's disease, and Still's can, in kids and adults, affect all races, all countries. But you don't have a lot of reports in non white populations.

It may be harder to diagnose, since it's a skin based diagnosis, in many. Fifty eight percent, about fifty seven sorry, fifty eight patients, fifty seven percent were adults with Still's. And you know, the whole thing between the EMA and the FDA is that now we're just taught and the EULAR guidelines say it's no longer systemic JIA and adult Still's disease. It's now Still's disease, and it's kids and adults. And it's the same disease accepted by the EMA and the FDA and endorsed by EULAR.

Well, this report kind of says something different. It says that there were differences between kids and adults, that, the female incidence was lower in kids, thirty six percent, versus adults, seventy one percent. In global studies, large cohort studies, it's fiftyfifty male female. They said kids were more likely to have the typical Still's rash, one hundred percent, versus only twenty nine percent in adults. Again, bigger studies, bigger cohort studies basically say typical Still's rash is about eighty plus percent.

They found something odd. Coronary artery dilation in sixteen percent of kids with Still's and none with adults. That sounds to me more like, you know, Kawasaki's disease than Still's, but nonetheless that's what they're reporting. MAS was more common in kids, fifty two percent versus nine percent. The general numbers are a little bit higher in kids, maybe as much as, you know, thirty percent, forty percent, and about a little bit behind, but close to that number in adults.

And adults had significantly more inflammatory polyarthralgia. I don't think arthralgia is a criteria for Still's. Arthritis is. Polyarthralgia is. Inflammatory polyarthralgia, I don't know, ninety one versus thirty two percent difference.

And adults had more lung disease, fifty one percent versus four percent. I throw it out there because it's different. It's at odds with some of the existing literature. It does come from The Caribbean, and it does come from a predominantly non white population. You do with it what you may.

We've talked a lot about GLP-one. I put up a post this week about warnings about surgery in patients who are taking GLP-1s. I encountered this recently, meaning that if you have a patient that's on a GLP-one agonist for whatever reason, and they need surgery, they won't do surgery or give general anesthesia if the patient just took the GLP-one drug, because they work by delaying gastric emptying. And with that in play, the anesthesiologists are a little bit wigged out over the possibility that there could be aspiration during or after surgery. So, I looked this up in several large studies.

First off, there is no firm recommendation. What I've heard from anesthesiologists is that you need to be off the drug for probably two weeks, but they want at least one week. Many studies have done have looked at not many some studies have looked at, the amount of residual gastric contents in the stomach in patients who are on GLP-one, And it's much higher, if you're on the drug than if you're not on the drug. It's like fifty, sixty percent versus around ten percent. And that's clearly, an issue.

They don't want gastric contents if they're going to put you on general anesthesia and lay you down. But the evidence that being on a GLP-one results in higher rates of aspiration pneumonia, that data is not in, but there are very few studies that have the numbers to adequately look at that. So this remains more of a real big concern, but it can get in the way of especially elective surgery. Advise your patients appropriately. Sarcopenia a lot in play.

We had a good lecture at RheumNow Live on sarcopenia in adults in our rheumatoid arthritis pod. This study of one hundred and thirty eight young adults with inflammatory arthritis, and these were young adults with either JIA, SPA, and RA, they found sarcopenia, low muscle mass, in forty seven percent. What? Really? I think that's a shocking number.

Again, using multivariate analysis, predictors of sarcopenia included BMI, BMD, vitamin D levels and HAC scores all being contributors. Oh my. A veteran study of almost twenty seven thousand RA patients looked at the risk of multiple myeloma. We've talked a lot about cancer. I got a bunch of abstracts after this about cancer.

In this study, on twenty seven thousand RA patients, the risk of myeloma did not go up with the use of biologic or targeted synthetic DMARDs or conventional DMARDs, even though thirty percent were on a biologic or targeted synthetic. And they had almost 200,000 patient years of follow-up. Again, the rate was zero point three seven versus zero point four two per 1,000 patient years. The hazard ratio is not elevated, so that's kind of interesting. I think maybe the biggest report this year came out of the just recently completed I think it ended yesterday or the day before the American Academy of Dermatology meeting.

There was a late breaking abstract on icotrokinra? Is that the name of IKEA furniture, or a Pokemon character, or a new drug? Let's go with new drug. It's a new oral IL-twenty three inhibitor that J and J is investigating, and they reported the results at the AAD meeting of a phase three study called the ICONIC LEAD study, where itrokinra was superior to the TYK2 inhibitor, ducravacitinib, at total skin clearance (sixty five percent versus eight percent) and PASI ninety fifty percent versus four percent at week fifteen in an almost seven hundred patient study of patients with moderate to severe plaque psoriasis. Again, an oral IL-twenty three (I think there's three IL-twenty three injectable IL-twenty three inhibitors), and they're burning it up in the psoriasis world, and they're doing well in our world in psoriatic arthritis as well.

Will this be a game changer in rheumatology? It's just going into trials in rheumatology. But this is the preliminary data, it's not yet in manuscript form, so we'll have to wait and see. I like this report about PIPSA and NIPSA. It reminds me of the report about Pira and NIRA.

PIPSA stands for persistent inflammatory psoriatic arthritis. NIPSA stands for non inflammatory psoriatic arthritis. And the issue is, if your patient has psoriatic arthritis, do they have non inflammatory disease, which is identified as having normal sed rate CRP? They probably have obesity, mechanical pain, osteoarthritis, fibromyalgia, secondary post inflammatory damage, or central pain mechanisms in play. Whereas those with inflammatory persistent inflammatory, they're going to have synovitis, inflammatory markers, etc.

This is gigantically important in: number one, knowing where you're going to go with your next therapy, right, and what you're going to focus on. And this applies to RA. It's come up in RA discussions when talking about difficult to treat RA, D2T D2T RA. It's now going to come up in discussions in treating difficult to treat PSA. And this is a key first line decision that you have to make in difficult to treat patients: Is it non inflammatory or inflammatory disease?

And then act accordingly with your therapeutic plan. I like this report. An important study was announced by BMS this week, Bristol Myers Squibb, on their phase three POETK PSA two trial. That's ducravacitinib, so TYK2, versus aprimolaz versus a placebo in patients with active PSA. They showed that obviously the TYK2 inhibitor, ducravacitinib, did very well at week sixteen versus placebo: 54 versus thirty nine percent.

That was significant. AEs leading to discontinuation were one percent for placebo, two percent for dukavacitinib, but ten percent for apremolast. A positive study in psoriatic arthritis patients with what appears to be superiority to aprimolast. And the question is: Where are you positioning these drugs? Do gravisitinib, the TYK2 inhibitor in psoriatic arthritis?

Again, it's not yet approved, but we do need to see these kind of studies to know where we're going to use it, because we seem to have already made our decisions about where we're using aprimelast in psoriatic arthritis. I like this report, this week about hydroxychloroquine. It's sort of a meta analysis in review, and I must say the authors of this paper kind of represented you very, very well. The paper was entitled Hydroxychloroquine in Sjogren's Syndrome, and it reflected your beliefs. And I'm talking about you in general, which is different than me specifically.

You in general tend to believe that, you know, there's a lot of drugs we can use for Sjogren's syndrome, and that's not true at all. And they kind of jumped around and said some, you know, kind of highlighted some things that were positive. But if you read the paper, despite the widespread use of hydroxychloroquine in Sjogren's syndrome, there's no good data that showed that hydroxychloroquine works in Sjogren's syndrome in the three randomized controlled trials showing no benefit. But there was, you know, for you believers, retrospective and open label, meaning goofy, less reliable studies that said it might could work. Again, do with this report what you may.

But it supports my contention that we need better drugs for Sjogren's syndrome. I now have three reports on cancer. I'll begin by saying last week I think I talked about a study of JAK inhibitors and a bunch of biologics showing no association with cancer in a large cohort study. Okay, that seems reasonable. In a meta analysis of cancer risk in patients taking abatacep or placebo or TNF inhibitors: 18 RCTs, 10 long term extensions, 15,000 patient years of abatacep exposure.

There was no significant increase in malignancy for abatacep versus placebo cancer rates. In fact, it was a little bit lower, forty two percent lower, or abatacep versus TNF. And cancer rates with eitheror here. And again, this was lower at twenty eight percent lower. There was some observational data, which we again would say is less reliable than head to heads, that suggest that it might be a little bit higher versus other biologic or other non TNF biologics, but not against conventional DMARTs.

So, again, it goes along with the idea that these drugs don't really seem to cause much in the way of cancer. Depends on, in these studies, on where the drugs are being used. They're seldom being used first line. Which is the most ideal situation to study this question? The Danish registry, the DAN BIO Registry, looked at 22,000 new drug starts with biologics, and basically, and again, almost 100,000 patient years, fourteen hundred cancers identified, The overall cancer risk with either new drug starts with tocilizumab or ceruleumab or abatacid or rituximab showed no significant increase hazard ratios ranging from 0.71 to 1.1 if you compare that to either TNF exposed patients or biologic DMAR naive real world RA patients.

And lastly, just to confuse you a little bit, here's a report from JAMA says there is an increased risk. But it comes with a caveat: a retrospective US administrative claims study observational administrative claims. You don't know why they're using it. You don't know if they're even getting the right drug, but the numbers are big. These are overall twenty five thousand three hundred and five RRA patients, seventy percent of whom were on a TNF inhibitor, ten percent on a JAK inhibitor, eight percent on Abitacin, four percent on either an IL-six or Rituximab.

And in this study, they did show a significant increase compared to TNF exposure for rituximab, abatacept and JAK inhibitors, as far as new incident cases of cancer, with the rate being: hazard ratio of one point nine one for rituximab, one point four seven for abatacem, and one point three or something for JAK inhibitors. And those were significant. But even the authors said that the way these drugs were being used as second, third, fourth line drugs in patients resistant to first and second line drugs, this likely represented a channeling bias as they were coming along in the treatment scheme late, you know, and after year one or after year two. So, you have to understand or look at this data, and again, I think I've said it here before: treat your RA patient, your PSA patient, as if they don't have cancer. Let someone who treats cancer worry about the cancer.

If they're going to tell you your drugs are a problem, they're a knucklehead, don't know what they're talking about, then give me a call and I'll call and yell at them. But again, I know it's a very, difficult discussion to have with patients. Patients are more concerned about their cancer than they are about their arthritis. Patients don't want to blame their cancer on something when they don't know why they got it. It's easy to blame the drug when there's no evidence that the drug caused the problem.

So, and again, my bias there is based on who gets these drugs? The patients with the worst possible disease. That's what happened early on in TNF inhibitor development. The worst possible patients got on these drugs. And then with the IL-6s, the abataceps, and the B cell drugs, and everything else, the JAK inhibitors, you got on those after you failed everything before it.

So, the worst possible patients: disabled, debilitated, with high inflammatory burdens. These are high cancer risk patients. My last report two last reports are combination biologics safe? You know, it's a hot button issue. Artie Cavanaugh talked about it at RheumNow Live.

There's studies in play in psoriasis and in inflammatory bowel disease that are looking at combination biologics. This particular report, I think, comes out of France, where it's looking at observational cohorts. And so, forty two thousand patients with immune mediated inflammatory disease, so that's R, A, PSA, IBD, a lot of IBD, Actually, half of them were IBD. They found one hundred and twenty five patients taking one hundred and thirty different combination therapies. And that was over a five year span from 2017 to 2022.

So somewhat recent. Half the patients had IBD, twenty three percent had autoimmune disease, or CTD. I don't know what that means. That's kind of I mean, again, that's dead word society, right? They're not supposed to be using that word term anymore.

And fourteen percent had inflammatory myopathy, eleven percent with vasculitis. High rates of serious infections: severe infections twenty four percent, neoplasia four percent, five point six percent deaths. The one year total cumulative incidence of serious adverse events was twenty nine percent. The cumulative incidence at one year of combination therapy of severe infections was twenty four percent, and SAEs were higher with a combination of abatacep with a JAK inhibitor hazard ratio 6.81, almost seven fold higher. An IL-one drug with anything else, almost a five fold higher rate, has a ratio of 4.8.

And an anti CD20 based therapy has a ratio of four, four fold higher. You'll notice this week that I'm always late for everything. You know, I'm going be late for my funeral, wedding, my writing. The 2024 Rheumatology Year Interview it's up, and you can look at it if you're interested. A few caveats from that: this year or last year, the FDA did approve 50 new drugs.

There were two new genetic therapies, gene based therapies. There were no new rheumatology drugs, and that's like the third year in a row. No new rheumatology drugs. Let me say that aloud: Hello. What's going on?

I don't like being ignored or my patients being neglected. But there were a number of new rheumatology indications led by bimekizumab, previously approved in 2023 for plaque psoriasis, approved in, 2024 for use in PSA, non radiographic axial spondyloarthritis and ankylosing spondylitis. And that's a welcome addition to the IL-seventeen world of therapies. Upadacitinib was also approved this past year in 2024 for active polyarticular JIA and pediatric PSA, and we're talking about amongst these pediatric patients aged two to 18. There were a lot of new biosimilars, as you know.

I mean, the gauntlet of adalimumab biosimilars were introduced in 2023. There was one new adalimumab, another new adalimumab biosimilar in 2024, bringing the total up to Humira plus 11 adalimumab biosimilars. We owe. But I think the big eye opener for me was that there were 19 new biosimilars approved, six of whom were ustekinumab biosimilars, Stellara biosimilars, and there was one IL-six biosimilar. There are based on tocilizumab biosimilars, making a total now of three tocilizumab biosimilars going by the name of tofidence, tyene and avtosma, if that interests you.

Right now, in The United States, there are, I think, 50 biosimilars that are in play, approved by the FDA, and 30 of them are for rheumatology drugs. The rest of the article talks about advances in AI, sort of the slow march, maybe somewhat disappointing, development of biosimilars. The FDA wants biosimilars. You want biosimilars. I don't think we got a biosimilar anywhere.

But they're coming, and people are working at it, so maybe we'll see biosimilars. I give a paragraph to steroids and all the talk about steroids still a big topic of concern. Another big issue of concern is cannabis. Widespread use. Many, many states approving it.

Yet we have no guidelines. Yet there are reports of safety: cardiac safety, liver safety, risk of death kind of a safety issue. And then I end with what I'm calling the heartbreak of osteoarthritis. Like, it is the biggest disease worldwide, and we've got nothing. And why are we not developing more drugs for osteoarthritis?

Yeah, I go to ACR, EULAR every year, and there's some, again, new drug that I can't pronounce, and I'm not sure if it's a Pokemon character, an IKEA furniture part, or a new drug, but they never get beyond phase three, and, and that's a problem. But let's end on a happy note. Here's a good quote from Margaret Mead. Never doubt that a small group of thoughtful, committed citizens can change the world. Indeed, it's the only thing that ever has.

I'm relying on you and a few friends to change the world. We'll see you next week.