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Hello everyone. We're two days away from the start of ACR.
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That would make this November the 6, 2026.
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And of course, this is the RheumNow podcast. I'm Jack Cush with RheumNow.
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This week, a positive spin on seronegative RA, playing the long game with stem cell transplants in scleroderma, and playing the numbers in rheumatology.
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We've got a lot of numbers to throw out at you today.
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Let's begin with the one big regulatory action this week, and that was the FDA approved an IL-23 inhibitor, tildrakizumab, from Sun Pharmaceuticals for use in psoriatic arthritis that is active.
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This makes the third IL-23 inhibitor. Tildrakizumab is also known as Ilumya.
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And the indication is active psoriatic disease.
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We know that this IL-23 inhibitor is also approved for plaque psoriasis, and that's for people who are candidates for systemic therapy or phototherapy.
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But now it's here for us rheumatologists.
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We have now three — we have guselkumab and risankizumab.
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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.
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They want to be blockbuster billion-dollar drugs.
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And now we have another IL-23. Are they going to get into the big money game on television in promoting their drugs?
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Those drugs were doing very well in sales from what I understand.
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Is this a science game or is this a marketing game? Such is life in medicine.
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The dosage in active psoriatic arthritis is 100 milligrams given every 12 weeks.
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Infection is the usual warning. You do have to test for TB prior to going on the drug.
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Although again, IL-23 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.
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But I think you do it with most of your biologics.
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There is an increased risk of serious infections as well.
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You're supposed to avoid the use of this biologic in patients who are getting live vaccines.
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Not a lot of experience on this in pregnancy.
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The drug is an antibody so it crosses the placenta.
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Peak levels are seen in animal models probably during the third trimester.
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The effects of this on the infant and fetus are unknown.
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It is found in breast milk. The other interesting thing I found in looking at the package insert on this is that there's a limited amount of exposure and use in the elderly.
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So of the 481 psoriatic arthritis patients exposed to the usual dose of tildrakizumab in the phase 2 and phase 3 trials, only 86 were over the age of 65.
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And while they noted no significant difference in safety or efficacy in that cohort of 86 versus the other 400 under the age of 65, I think that I'd like to see some more data on the use of this particular IL-23 inhibitor in the elderly.
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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 days.
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Okay. There was a nice review of fibromyalgia and therapies ahead from Medscape.
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We put that up this week. The headline was that there are four fibromyalgia drugs approved in the United States and none of those four are approved by the EMA in Europe.
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And it has to do with just sort of the regulatory process.
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Now the newest one, which is sublingual cyclobenzaprine, I don't think has yet been submitted to the EMA in Europe.
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But the drugs — pregabalin approved in 2007, duloxetine 2008, milnacipran — Savella — in 2009 — they didn't fare very well in front of the EMA and they're not approved there.
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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.
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And we don't often publish enough on fibromyalgia in rheumatology, and certainly on our own website.
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Exagen is a company that makes a lot of interesting labs.
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They did a study looking at a number of different labs that you can do for rheumatoid arthritis and studied them in 192 established RA patients versus 383 controls.
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They did the CCP2, they did rheumatoid factor IgA, IgM, I think IgG, they did PAD4 antibodies IgA and IgG.
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And overall they said some things that you already know, but what they wanted to say was in people who are seronegative there may be some value in ordering these other autoantibodies — not the IgM rheumatoid factor, but maybe IgA and IgG, maybe the PAD4 antibodies as well.
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What they did show was that RA was strongly associated with CCP2, the odds ratio being 110-fold — again speaks to the strength both in sensitivity and especially specificity for CCP antibodies, also known as ACPA.
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Rheumatoid factor — the many different forms that they tested for, IgA, IgM — had roughly a sevenfold increased association with RA.
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PAD4 was 3.5- to sixfold. And when they looked at the CCP-negative population amongst that 192 RA patients, only PAD4 and rheumatoid factor had an odds ratio significantly elevated, saying it was associated with seronegative. PAD4 was 2.87, rheumatoid factor 2.2.
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What does that really mean? The differential gain in ordering especially a PAD4 IgG antibody was 0.02 to 0.04 in area under the curve.
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To be significant, you'd have to be like 0.5.
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So there's a little bit of an advantage.
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Do I order these tests in my seronegatives?
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I do not, unless they seem hellbent on wanting to know why they have rheumatoid but not a positive rheumatoid factor or CCP.
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I don't think I need to explain that by ordering more labs.
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But I think the analysis tells you again the relative importance, and it does sort of answer the question as to whether you should be doing these tests or not.
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I think the answer is no. I think that wasn't the point of the paper, however.
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There was a good review by Denahrio and colleagues on seronegative RA that made a lot of the same points that I make in my seronegative RA lecture.
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And I think it's worth just bearing — to repeat that here.
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One, that seronegative RA is biologically a different animal, right?
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And that's worth noting. It's different.
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It's a different animal in many different factors, but mainly the biology.
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It's also a different animal in that if they're seronegative, they may well have another diagnosis, right?
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And that each visit is your opportunity to reassess whether they could have another diagnosis.
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And you know the question is whether a seronegative, as was indicated by the previous study, should have testing with unconventional autoantibodies such as PAD4, CarP — there's a whole bunch of them, SA and others.
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Again, I don't think so. I think there's small gain on that.
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But what we do know is patients who are CCP-negative and IgM rheumatoid factor-negative are less likely to have erosions, but at presentation they have just as severe a disease as do the seropositives.
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So seropositivity imparts not greater disease activity but a greater risk of erosive disease, and that's really important.
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Seronegatives have less erosive disease, but they can be really bad at the outset.
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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.
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So they're going to have more severe disease, or equally severe disease, if such is the case.
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By no means is this a benign disease. You do get erosions.
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You do have the same bad outcomes. But maybe patients with seronegative have a greater chance of drug-free remission, up to as high as 40%.
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And then last, the last factor had to do with seropositive versus seronegative when it comes to drug responses.
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We've talked before about seropositive patients tending to respond better to rituximab, abatacept, maybe tofacitinib and JAK inhibitors.
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In this analysis they said that there are weaker drug responses if you're seronegative to methotrexate, rituximab, abatacept, and tofacitinib.
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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 where you're trying to prevent the development of RA — and it didn't work.
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Methotrexate wasn't good at preventing RA in that study.
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However, an asterisk says it was good at preventing progression to RA, but only in seronegatives.
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I think this supports my first point: seronegative RA is biologically a different beast than is seropositive.
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I don't want either. If I had to take one, I probably would take seronegative and hope that it's going to be another diagnosis on my third, fourth, or eighth visit.
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A Spanish study looked at 5,000 hospitalized GCA patients and looked at the frequency of aortic aneurysms.
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It was only 1% at baseline, and another 1.8% developed aortic aneurysms with prolonged follow-up.
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I think the follow-up was a few years here, not really prolonged.
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The risk was higher in males and in patients who were smokers who had a diagnosis of GCA.
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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-1 inhibitor or an IL-6 inhibitor.
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There was a report this week about tocilizumab.
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It was an analysis of a bunch of patients treated with tocilizumab with adult-onset Still's disease.
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40 patients with adult-onset Still's treated with 4 to 8 milligrams per kilogram given every four weeks.
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I want to stress to you that that's what they found in this study.
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You are allowed to use 8, and in the pediatric literature the trials — the TENDER trial that tested tocilizumab in systemic JIA — used doses up to 12 milligrams per kilogram.
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Point being: for active systemic Still's, use a high dose.
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Use at least 8 milligrams per kilogram would be my recommendation.
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Anyway, in this analysis the 12-month clinical remission rate was 55%.
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The six-month rate of clinically inactive disease was 62%.
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And using tocilizumab led to big-time drops in CRP, sed rate, ferritin, and daily prednisone use dropped by 91%, from a median of 50 mg per day to 4.4 mg per day.
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At the end of this study period, whatever it was, the retention rates were two-thirds, 63%.
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Serious adverse event rates — MAS still occurs in people on tocilizumab.
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It happened in the TENDER trial. They had — I think I want to say it was 112 patients — I think there were two cases of MAS that occurred in people that were still on — still on MAS.
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So while that may be a treatment for MAS, it can still happen when they're on an IL-6 inhibitor.
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Lymphoma occurred 2.5% of the time, and that's worrisome to me.
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One, I don't think tocilizumab causes lymphoma.
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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 FUO.
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So were those real lymphomas, or were those lymphomas presenting as Still's that did get treated with tocilizumab and maybe even responded?
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For all you know — I've seen lymphoma respond to IL-1 inhibition when it was being considered as having Still's disease.
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But yeah, people with that multi-system disorder, lymphadenopathy, splenomegaly, crazy-looking labs, gigantically inflammatory profiles — you should think about lymphoma, especially in someone who instead of having generalized lymphadenopathy has focal adenopathy.
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Biopsy it. If the hematologic picture is strange and not typical of Still's, get a bone marrow biopsy.
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You don't want to miss a lymphoma diagnosis when considering Still's.
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Two last reports on systemic sclerosis. A Japanese retrospective cohort study showed that using adjunctive tofacitinib was really beneficial on the GI tract.
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This was 50 patients with systemic sclerosis who had esophageal symptoms.
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They showed that they were on other immunosuppressives and they either gave them placebo or tofacitinib for 24 weeks.
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Tofacitinib was associated with significant improvement in lower esophageal sphincter pressures.
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It was also significant in lowering the modified Rodnan skin scores and in lowering IL-6 levels, as would be expected of the drug.
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So I put this up there because — first off this is not a controlled trial, there's not an active comparator here — well, there is a placebo comparator here.
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It's a small trial, I guess, might be the one limitation of the study.
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But I think there's a growing body of literature about JAK inhibitor utility in patients with systemic sclerosis, just as I think there's good growing literature about rituximab in systemic sclerosis, especially the diffuse kind.
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So I'm encouraged by this data and I think you should be as well.
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There was another study this week about 80 patients with systemic sclerosis — a 10-year follow-up study of those who received autologous bone marrow transplant, abbreviated HCT.
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The median follow-up was 9 to 10 years. These people received stem cell therapy between 2012 and 2016.
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Progression-free systemic sclerosis survival was seen in 81% at two years.
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That's really good, because these people — if they're sick enough to get stem cell, they're really in a bad way.
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They're going to have a high mortality rate.
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But at 10 years, progression-free survival was 60%.
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The overall for the whole cohort was 71%.
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43% 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.
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Modified Rodnan skin scores improved significantly from 24 — a high score — down to 6 at 5 years and down to 5 at 10 years.
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Similarly, lung function improved — median FVC was 72% predicted at baseline and 71% at 10 years, suggesting no progression.
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So again I think really encouraging data.
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We have seen this stem cell transplant data in the past and always said, hmm, that's really interesting.
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Most of us don't have access to this. You have to send your patients to specialized centers.
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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.
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One did go into renal crisis but did not end up with only mild renal impairment in the long run, and lived a long, long time.
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So I think that now there's a lot of excitement about CAR T-cell therapy with systemic sclerosis, and that's justified.
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But we don't have control data. We don't have long-term data.
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We do have control data and long-term data with autologous bone marrow transplants, and we should still be considering that.
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That's it for this week on the podcast. Again, starting Sunday — Sunday through Wednesday — we're going to 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.
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My recommendation is go to RheumNow.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.
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If you want to follow everything as it's coming out like the ticker tape, then just follow it as it's listed.
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If you're a patient — or a person that's only interested in scleroderma, or in lupus, or in obesity, or fibromyalgia — we're covering that as well.
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Click on the filter and you'll see just all the fibromyalgia reports.
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We've got something interesting and cool in the upper right-hand corner where there's an AI tool that you can ask what's going on at the ACR — what are the big trends in PsA from ACR this week — and it'll give you a nice little AI synopsis there.
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My recommendation on how to follow this fire hose of information that we're going to be putting out over a 3-and-a-half-day period is: number one, tune in to watch the daily recaps.
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Starting Sunday and for 4 days — Sunday, Monday, Tuesday, Wednesday at 6:00 p.m.
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— we're going to have four of our faculty members review the best thing that they saw that day.
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I think that's a really great way to see what's going on.
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Secondly, there are two articles I write every day at the meeting.
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One is the day one report, and the second will be the ACR best synopsis as chosen by our covering faculty.
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Those are pretty short reads telling you what was the hot item of the day — also something that would be covered on the recap.
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The other way would be after the meeting to tune in to Artie Kavanaugh and me on the Friday after we get back.
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I think that's the 16th — I want to guess, but it could be the 13th.
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And again at 7:00 p.m. Eastern in that same slot where we have the recaps and the panels, Artie Kavanaugh and I are going to do a rheumatology roundup and give you our best picks of the meeting.
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And then the last thing to take in all the good stuff, the hot stuff — we're going to have five topic panels that will start to roll out the week after the ACR.
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I think that's the 16th on Monday. All as Tuesday night rheumatology sessions, meaning 7:00 p.m.
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Eastern. Those are going to run live from Monday, Tuesday, Wednesday, Thursday, and Friday.
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And the topics will be PsA, fibromyalgia, RA, lupus, and ILD topic panels.
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Tune in. We'll talk during the meeting. Take care.
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