3 x IL-23 = IL do Better (11.6.2026) Save

Hello everyone, we're two days away from the start of ACR. That would make this 11/06/2026. And, of course, this is the RheumNow podcast. I'm Jack Cush with RheumNow. This week, a positive spin on seronegative RA, playing the long game with stem cell transplants in scleroderma, and playing the numbers in rheumatology.

We've got a lot of numbers to throw out at you today. Let's begin with the one big action this week, and that was the FDA approved an IL-twenty three inhibitor, Tildrekizumab, from Sun Pharmaceuticals, for use in psoriatic arthritis that is active. This makes the third IL-twenty three inhibitor. Tildrekizumab is also known as ILUMYA and the indication is active psoriatic disease. We know that this IL-twenty three inhibitor is also approved for plaque psoriasis, and that's for people who are candidates for systemic therapy or phototherapy.

But now it's here for us, rheumatologists. And we have now three. We have gaselcumab and rizenkizumab. And the interesting thing about this is, those two products in The United States are spending a ton of money on direct to consumer advertising. They want to be blockbuster billion dollar drugs.

And now we have another aisle 23. Are they gonna get into the big money game on television in promoting their drugs? It's... And those drugs were doing very well in sales from what I understand. Is this a science game or is this a marketing game?

Such is life in medicine. The dosage in active psoriatic arthritis is one hundred mg given every twelve weeks. Infection, as usual, warnings. You do have to test for TB prior to going on the drug, although, again, IL-twenty three inhibition really shouldn't be a major risk factor for TB and TB reactivation, but it was done as part of the clinical trials, which is why it's in the label and why you have to do it. But I think you do it with most of your biologics.

There is an increased risk of serious infections as well. You're supposed to avoid the use of this biologic in patients who are getting live vaccines. Not a lot of experience on this in pregnancy. The drug is an antibody, so it crosses placenta. Peak levels are seen in animal models probably during the third trimester.

The effects of this on the infant and fetus are unknown. It is found in breast milk. The other interesting thing I found looking at the package insert on this is that there is a limited amount of exposure and use in the elderly. So of the four eighty one psoriatic arthritis patients exposed to the usual dose of tildrakizumab in the phase two and phase three trials, only eighty six were 65. And while they noted no significant difference in safety or efficacy in that cohort of eighty six versus the other four hundred 65, I think that, I'd like to see some more data on the use of this particular IL-twenty three inhibitor in the elderly.

A lot of our patients, who are older do need these newer drugs as much as the younger ones. The half life of the drug is 23. Okay? There was a nice review of fibromyalgia and therapies from Medscape. We put that up this week.

The headline was that there's four fibromyalgia drugs approved in The United States, and none of those four are approved by the EMA in Europe. And it has to do with just sort of the regulatory process. Now, the newest one, which is sublingual cyclobenzaprine, I don't think has been yet submitted to the EMA in Europe. But the drugs pregabalin, approved in 2007, duloxetine, 2008, milnacipran, Sevella in 2009. They didn't fare very well in front of the EMA, and they're not FDA approved.

The review goes through other therapies that are advocated, that are off label uses, including some stuff about Naltrexone and whatnot, which I don't think is an endorsement. But, it is a good review, and we don't often publish enough on fibromyalgia, in rheumatology and certainly on our own website. Exagen is a company that makes a lot of interesting labs. They did a study looking at a number of different labs that you can do for rheumatoid arthritis, and studied them in one hundred and ninety two established RA patients versus three eighty three controls. They did the CCP2, they did rheumatoid factor IgA, IgM, I think IgG.

They did PADI-four antibodies, IgA and IgG. And overall, they said some things that you already know. But what they wanted to say was, in people who were seronegative, there may be some value in ordering these other autoantibodies, not the IgM rheumatoid factor, but maybe IgA and IgG, maybe the PAD IV antibodies as well. What they did show that RA was strongly associated with CCP2, the odds ratio being one hundred and ten fold. Again, speaks to the strength, both in sensitivity and especially specificity for CCP antibodies, also known as ACPA.

Rheumatoid factor, the many different forms that they tested for, IgA, IgM, had roughly a seven fold increase association with RA. PAD four was 3.5 to six fold. And when they looked at the CCP negative population amongst that one hundred and ninety two RA patients, only PAD IV and rheumatoid factor had an odds ratio significantly elevated, saying it was associated with serum negative. PAD four was 2.87, rheumatoid factor 2.2. What does that really mean?

The differential gain in ordering, especially a PAD four IgG antibody, was point zero two to point zero four in area under the curve. To be significant, you'd have to be like point five. So there's a little bit of an advantage. Do I order these tests in my seronegatives? I do not.

Unless they seem hell bent on wanting to know why do I have rheumatoid but not a positive rheumatoid factor or CCP. I don't think I need to explain that by ordering more labs, but I think the analysis tells you, again, relative importance, and it does sort of answer the question as to whether you should be doing these tests or not. I think the answer is no. I think that wasn't the point of the paper, however. There was a good review in a, by D'Onofrio and colleagues on seronegative RA made a lot of the same points that I make in my seronegative RA lecture, and I I I think it's worth just bearing that to to repeat that here.

One, that seronegative RA is biologically a different animal. Right? And that's worth noting. It's a different animal in many different factors, mainly the biology. It's also a different animal in that if they're seronegative, they may well have another diagnosis.

Right? And that each visit is your opportunity to reassess whether they could have another diagnosis. And, you know, the question is whether a seronegative, as was indicated by the previous study, should have testing with unconventional autoantibodies such as, PAD four, CARB P. There's a whole bunch of them, SA and others. Again, I don't think so.

I think there's a small gain on that. But what we do know is patients who are CCP negative and IgM Rheumatoid Factor negative, they are less likely to have erosions, but at presentation, they have just as severe a disease as do the seropositives. So seropositives imparts not greater disease activity, but a greater risk of erosive disease. And that's really important. Serone negatives have less erosive disease, but they can be really bad at the outset.

And the reason for that is because you don't have the added value of a positive CCP, or rheumatoid factor, you've got to work harder on other features of RA to call it RA. So they're going to have more severe disease, or equally severe disease, if such is the case. By no means is this a benign disease. You do get erosions, you do have the same bad outcomes. But, you know, maybe patients with seronegative have a greater chance of drug free remission, up to as high as forty percent.

But, and then the last factor had to do with seropositive versus seronegative when it comes to drug responses. We've talked before about seropositive patients tend to respond better to rituximab, abatacet, maybe tofacitinib and JAK inhibitors. In this analysis, they said that there are weaker drug responses if you're seronegative to methotrexate, rituximab, abatacip, and tofacitinib. And the methotrexate story is probably best explained or reviewed when you look at the REACH data, the clinical trial in clinically suspect arthralgia patients, we were trying to prevent the development of RA, and it didn't work. Right?

Methotrexate wasn't good at preventing RA in that study. However, asterisk says it was good at preventing progression of RA, but only in seronegative. I think this supports my first point. Seronegative RA is biologically a different beast than is seropositive. I don't want either.

If I had to take one, I probably would take seronegative and hope that it's gonna be another diagnosis on my third, fourth, or eighth visit. A Spanish study looked at, five thousand hospitalized GCA patients and looked at the frequency of aortic aneurysms. It was only one percent at baseline, and another one percent, zero point eight percent, developed aortic aneurysms with prolonged follow-up. I think the follow-up was a few years here, not really prolonged. The risk was higher in males and in patients who were smokers who had a diagnosis of GCA.

We do know that patients with Still's disease in the kid or the adult, the first line therapy these days, you're going to use steroids, and that's okay, but really the first line therapy should be an IL-one inhibitor or an IL-six inhibitor. There was a report this week about tocilizumab. It was an analysis of a bunch of patients treated with tocilizumab with adult onset Still's disease. Forty patients with adult onset Still's treated with four to eight milligrams per kilogram given every four weeks. I want to stress to you that that's what they found in this study.

You are allowed to use eight, and in the pediatric literature, the the TENDER trial, that tested tocilizumab in systemic JIA used doses up to twelve mgkg. Point being, red hot active systemic stills, use a high dose. Use at least eight mgkg would be my recommendation. Anyway, in this analysis, the twelve month clinical remission rate was fifty five percent, the six month rate of clinically inactive disease was sixty two percent, and using tocilizumab meant big time drops in CRP, sed rate, ferritin, and daily prednisone use dropped by ninety one percent from a median of fifty milligrams per day to four point four milligrams per day at the end of this study period, whatever it was. The retention rates were two thirds, sixty three percent.

Serious adverse event rates, MAS, still occurs in people on tocilizumab. It happened in the TENDER trial. They had, I think, I want to say it was one hundred and twelve patients. I think there were two cases of MAS that occurred in people that were still on MAS. So while that may be treatment for MAS, it can still happen when they're on an IL-six inhibitor.

Lymphoma occurred two point five percent of the time. And that's worrisome to me. One, I don't think tocilizumab causes lymphoma. It's worrisome to me because sometimes patients with Still's, the differential diagnosis is long, and cancer is always on the list. And lymphoma can present as FUOs.

So, were those real lymphomas, or were those lymphomas presenting as Still's that did get treated with tocilizumab, and maybe even responded, for all you know? I've seen lymphoma respond to IL-one inhibition, when it was being considered as having Still's disease. But yeah, people with that multisystem disorder, lymphadenopathy, splenomegaly, hepatomegaly, crazy looking labs, you know, gigantically inflammatory profiles, you should think about lymphoma. Especially in someone who has, instead of having generalized lymphadenopathy, but has focal, adenopathy, biopsy it. If the hematologic picture is strange and not typical of Still's, get a bone marrow biopsy.

You don't want to miss a lymphoma diagnosis when considering Still's. Two last reports on, systemic sclerosis. A Japanese retrospective cohort study showed that using adjunctive tofacitinib was really beneficial on the GI tract. This was fifty patients with systemic sclerosis who had esophageal symptoms. They showed that they were on other immunosuppressives, and they either gave them placebo or tofacitinib for twenty four weeks.

Tofacitinib was associated with significant improvement in lower esophageal sphincter pressures. It was also significant in lowering the modified Rodnan Skin scores, and in IL-six levels, as would be expected of the drug tofacitinib. So, you know, I put this up there because, first off, this is not a controlled trial. This is not an active comparator here. This is...

Well, is a placebo comparator here. It's a small trial, I guess. It might be the one limitation of this study. But I think there's a growing body of literature about JAK inhibitor utility in patients with systemic sclerosis. Just as I think that there's good growing literature about rituximab in systemic sclerosis, especially the diffuse kind.

So I'm encouraged by this data, and I think you should be as well. There was another study this week about 80 patients with systemic sclerosis, a ten year follow-up study of those who received autologous bone marrow transplant, abbreviated HCT. The median follow-up was nine to ten years. They showed that... And these people received stem cell therapy between 2012 and 2016.

Progression free systemic sclerosis systemic sclerosis and survival was seen in eighty one percent at two years. That's really good, because these people, if they're sick enough to get stem cell, they're really in a bad way. They're going to have a high mortality rate. But at ten years, progression free survival was sixty percent. The overall for the whole cohort was seventy one percent.

Forty three percent of the people were still alive at the end of the study, and the interesting thing was that they were alive and not requiring further immunosuppressive therapy at their last follow-up visit. Modified Rodnan Skin scores improved significantly from 24, a high score, down to six at five years and down to five at ten years. Similarly, ILD improved. Median FVC was seventy two percent predicted at baseline, and seventy one percent at ten years, suggesting no progression. So again, I think really encouraging data.

We have seen this, you know, stem cell transplant data in the past and always said, that's really interesting. Most of us don't have access to this. You have to send your patients to specialized centers. I've sent two of my patients in the past who did dramatically well. And they went because they had diffuse disease that was rapidly advancing.

One did go into renal crisis, but did not end up only with mild renal impairment in the long run, but lived a long, long time. So, I think that now there's a lot of excitement about CAR T cell therapy with systemic sclerosis, and that's justified. But we don't have controlled data. We don't have long term data. We do have controlled data and long term data with autologous bone marrow transplants, and we should still be considering that.

That's it for this week on the podcast. Again, starting Sunday, Sunday through Wednesday, we're gonna be covering the ACR, in a big way with a lot of tweets, a lot of articles, a lot of videos, a lot of podcasts. My recommendation is go to, roomnow.com or click on one of the emails during the ACR meeting and look at our new, ACR website where you can choose the information that you want to follow. You want to follow everything as it's coming out, like the ticker tape, then just follow it as it's listed. You want to...

You're a patient that's... A person that's only interested in scleroderma or in lupus, or in obesity, or fibromyalgia, we're covering that as well. Click on filter and you'll see just all the fibromyalgia reports. We've something interesting and cool in the upper right hand corner, where it's an AI tool that you can ask the question of what's going on with the ACR, what's the big trends in PSA from ACR this this week, and it'll give you a nice little AI synopsis there. My recommendation on how to follow this fire hose of information that we're gonna be putting out over a three and a half day period is number one.

Tune in to watch the daily recaps starting Sunday And for four days, Sunday, Monday, Tuesday, Wednesday at 6PM, we're going to have four of our faculty members review the best thing that they saw that day. I think that's a really great way to see what's going on. Secondly, you... Two articles I write every day at the meeting. One is the day one report, and the second one will be the ACR best synopsis as chosen by our covering faculty.

Those are pretty short reads telling you what was the hot item of the day, also something that would be covered on the recap. The other way would be after the meeting to tune in to Artie Cavanaugh and I on the Friday after we get back. I think that's the sixteenth, I wanna guess, but that could be the... I guess the thirteenth. And, again, at 7PM eastern in that same slot where we have the recaps and the panels, Artie Cavanaugh are gonna do a rheumatology roundup and give you our best 16 of the meeting.

And then the last thing to take in the the... All the the good stuff, the hot stuff, is we're going to have five topic panels that will start to roll out the week after the ACR. I think that's the sixteenth on Monday. All as Tuesday night rheumatology sessions, meaning 7PM eastern, those are going to run live from Monday, Tuesday, Wednesday, Thursday, and Friday, and the topics will be PSA, fibromyalgia, RA, lupus, and ILD Tune in, we'll talk during the meeting. Take care.