NME: New Molecular Entities (8.28.2026) Save

It's 08/28/2026. This is the RheumNow podcast. Hi, I'm doctor Jack Cush, executive editor of roomnow.com. This week on the podcast, we'll talk about vasculitis, scleroderma, new drugs in development, I call that new molecular entities, but let's begin with a report on aortopathies. You know, it doesn't come up much, but I encountered it this week in clinic, wanted to know, the differential diagnosis to aortitis.

Interestingly, there was a paper just published on this and, the list includes a number of things I did not know and I'm gonna rehash that for you here. Obviously, Takayasu's and giant cell arteritis has large vessel vasculopathies, but aortitis has been also described in IgG4a related disease, RA, lupus, spondylitis, scleroderma, relapsing polychondritis, Cogon syndrome, and Behcet's. The approach to take with these folks as far as, short of biopsy would be, imaging with CT angiography, MR and MRA. Usually, they're like MR and then PET CTs, FDG PETs. FDG PETs is really good at activity.

MRI is good at damage and CT it might be good at damage, but anyway, I think that, we do see a fair amount of this and need to use those tools. Speaking of new molecular entities, Spire is a company that's developing an anti TL1A antibody called SPY072 in RA. They reported their top line results, which some thought were disappointing, I thought were okay. It's a phase two trial, so you don't have to, hit home runs, you need to be consistently good. This is a study of their TLA1 antibody in RA patients, a hundred and thirty three RA patients, phase two.

They get two doses of SPY seventy two, and they showed it was better than placebo at a twelve week endpoint. ACR 20s were sixty three 58 versus forty three percent, that's a high placebo response, but the delta between the higher dose and placebo is 20 points. That's FDA approvable in my book. ACR fifty was thirty one and thirty eight, versus 19, that's certainly good and again, there's this trend of the lower dose doing better than the higher dose. It's roll of the dice, folks.

It's not really science, and and the DAS CRPs, which was our, I think, primary endpoint reduction in DAS CRP was minus 1.5 and minus 1.9, for the drugs and then minus 1.3. So, the delta there wasn't as great, but these drugs are the hot new thing in autoimmune disease drug development. You know, the hot new thing is CAR T and we'll talk about that, but they're further along. They're, I don't know, four or five of these in development that, I know of. Again, TL1A stands for tumor necrosis factor like cytokine 1A.

It binds to the DR3 depth receptor three on T cells and lymphoid cells, and in binding, it induces not only inflammation but also fibrosis, and we have so few drugs that are targeting fibrosis. IL-six inhibitors somewhat target fibrosis, but we have no anti fibrotic drugs. So, if this were to move along with these different companies, that would be encouraging. The drugs are being developed in inflammatory arthritis, RA, PSA, I believe, in ulcerative colitis and also, in scleroderma. So, hopefully we'll see a lot of these, presented at ACR, probably the early phase two studies like this one.

Another new drug, this one from China, envaramacitinib, also known as SHR-three zero two. Let's go with envaramacitinib, that's easier. It's a JAK1 inhibitor, from China. China's got a number of JAK1 inhibitors that they are developing. I think one is actually FDA approved for use in China.

This was a study of a phase two, maybe phase three, I guess there's an arm of it that will extend into their phase three and, they showed, you know, fairly interesting results here. Let me get to the data. So they did a study in, ankylosing spondylitis patients, they treated one hundred and eighty seven with four milligrams once a day, versus placebo, one hundred and eighty, what is it, one hundred and eighty seven patients are treated with four milligrams once a day versus one hundred and eighty six patients treated with placebo. Envamacitinib at week twelve has significantly better, ACR 20 responses, forty nine percent versus 29% and better, ASAS 40 responses, thirty two versus 18. That's ballpark for what's been described with certainly with JAK inhibitors in spondylitis.

They also showed other secondary outcomes that were superior, total back pain by visual analog score, night pain, ASDAS scores, and they showed that when you continue to draw the drug on through six months, that the responses were maintained. Other IL-one, I'm sorry, JAK1 inhibitors in development in China include, Zembrolizumab, that's in phase three, and we heard two years ago at ACR and EULAR about TLL-eighteen, that's a JAK1 TYK2 combination drug that beat tofacitinib head to head, that's in the literature was presented at the meeting. So again, interesting work being done out of China. Another drug in development is a CAR T therapy, CD19 CAR T cell, the COMPARE trial, it's called MIV cell, Mivocabagene autoleuca cell, let's call it MIV cell. This was a phase one, phase two, six patients, open label, the patients had to have RA, refractory disease, ACPA positivity, they had severe refractory disease.

They were given, they were treated with lymphodepletion, at the outset and then given MivCell and followed like thirty two to fifty two weeks. All of the patients, this was a safety study, so all the patients had cytokine release syndrome, but not too bad, like manageable. None of them had ICANS, more serious, or, serious adverse events in the limited follow-up they have. All of them had CD19 B cell depletion as a result of therapy, and that was brisk, like you'd expect, and all of them had a reduction in autoantibodies. They're, but not all of them, the autoantibodies like rheumatoid factor and APA went down a lot, but not to zero in all of them.

Efficacy was okay, you know, they started getting ACR20 responses by week twelve, but, you know, gigantic responses like you might have expected with a CAR T cell therapy, wasn't as much as we would hope for. Anyway, three out of six patients had an ACR seventy, and they had substantial reductions in -twenty eight CRP scores. They have 10 more patients that are in, development, but again, we're waiting for a real trial. You know, these are the early dose finding, show it safe kind of studies you got to do before, you know, you got to crawl before you run-in this game of CAR T. Mike Putman put up a great, tweet this week, actually an email this week, called CAR T reality check.

It's worth a click and looking at the numbers. I think the numbers are something like there's more studies than there are patients treated with CAR T, which is to say that in all of these burgeoning CAR T cell studies, they all have one, two, three patients, you know, they're not like Professor Schett's 19 patient experience and long term follow-up, they're all brand new. So, Mike's point was the hype is outrunning the evidence, and so he created a dashboard so that you can track what's actually happening in the wonderful world of CAR T cell, development. Few numbers, limited follow-up, again, I'm not as excited as you are and, that's because I'm a clinical trialist, I've been on the FDA advisory panel, I want to see the data. I want to see safety data first, which is what they're showing us, and it's good but it's not totally safe.

There's a lot of safety signals that are a little concerning here, but I want to see the data on performance with a comparator drug, active drug or placebo, and that hasn't happened yet. The VA has a study of four thousand patients with RAILD and they describe for you drug use in the VA system between two thousand and six and twenty twenty one. Up to three quarters of the patients have received prednisone. The first line therapies, are as you would expect, mycophenolate, azathioprine, rituximab, and cyclophosphamide. After the diagnosis of ILD in RA patients, use of those therapies went way up, right?

Methotrexate use was very low. Maybe the rheumatologists are listening to the pulmonologists. I don't. I would use methotrexate in these patients, but it was, depending on the cohort, it was less than twelve percent and after the diagnosis, methotrexate, which was being used, decreased by at least a third, if not a half. Drugs that increase after the diagnosis of, ILD, and with the reduction maybe of methotrexate use, were leflinamide, TNF, and abatacid.

In their study, the predictors of, ILD treatment in RA was the FVC, forced vital capacity, being ACPA or CCP positive and having an ILD diagnosis after 2012. I like that kind of study. I mean, it is retrospective, but it tells you the real world trends of what's going on in a system of excellent physicians who work at our VA medical centers. Another RA study looked at e cigarette use, and its association with incident RA and lupus. This comes from the All of Us Research Program, it's the nationwide program, almost a million patients, they collect data, they collect samples, they might be the largest genomics, database, that's out there.

This is a study that matched almost 16,000 e cigarette users, 16,000 e cigarette users versus non users, and they found that sixty six new RA patients and lupus patients were, amongst the patients who received e cigs and that had an incidence rate of one point four three per one thousand. Non users, the rate was less than one, point nine three per one thousand patient years, So, there's basically a fifty four percent increased risk of developing either RA or lupus with e cigarettes. We know cigarettes cause disease, worsen disease, worsen drug responses, etcetera, but they are driver of incident disease for many diseases. We do know that, secondhand smoke is a risk factor, as is environmental pollution. This is the first to show that e cigarettes are as indictful as those other environmental, toxins.

I like this study, that compares via meta analysis, systematic review, juvenile systemic sclerosis and adult systemic sclerosis. They surveyed the literature, 39 studies that had a comparison. The numbers were, what was it? Juvenile systemic sclerosis was nine thirty five, Adult systemic sclerosis was fifteen thousand, and guess what? Juvenile systemic sclerosis is worse, just like lupus.

Pediatric lupus is worse than adult lupus. Juvenile systemic sclerosis had more cutaneous disease seventy versus forty one percent, more overlap myositis, thirty three percent versus five, more arthritis, thirty three percent versus eighteen, more digital ulcers, fifty one percent versus twenty percent, and less renal crisis, Zero in the kids, six percent in the adults. But interestingly, overall juvenile systemic sources had a lower overall mortality. So when you look at those last two figures where juvenile systemic sources had less renal crisis, overall mortality. I think it speaks to the added problem of aging and additional comorbidities like hypertension and other comorbidities into some of the worse outcomes that we see in systemic sclerosis.

They're not there from the start. They may need time and they may be driven or fortified by, comorbidities. That's my take. Another good study that came out this week looked at whether you can use ultrasound of enthesitis in psoriasis patients to see if it might predict future development of psoriatic arthritis or give us some insights. This was, a study that specifically looked at aprimilast patients, with psoriasis and, it's a low number.

It was twenty patients with long standing psoriasis. They had a lot of nail and scalp disease. They had not yet received biologics or targeted synthetics and they were being put on a Primilast, and it was an open label study of a Primilast and a few things got better. It was the usual dose, thirty milligrams BID, six months study. They did enthesitis assessments by MRI and high res QCT.

That did not change. They found a minority with enthesitis signal by those two very exacting imaging measures did not change with a Primalas therapy over six months. Similarly, the PSAMRIS, this TESAMRIS, this is the, MRI validated tool for psoriatic arthritis, also showed no change in six months, and there were of course no new erosions and that might be a good thing, but there was no improvement, and the PASI scores did improve 11 to five were the means, and total joint counts improved from 3.2 to about 0.8. So there was, again, the sort of modest to moderate improvement and things that you'd like to see skin and joints, but at the end theseal level, with high res imaging, not benefit no benefit was seen, but then again, maybe there was a small benefit in that no worsening was seen, right? Even though some joints got worse.

Hard to interpret data like this, and I presented so that you can ponder it just as I am. A meta analysis this week of 61 studies, looking at whether exercise modulates inflammatory markers, and their overall, they showed evidence that, especially in chronic diseases, exercise does have an anti inflammatory effect with significant reductions in CRP, IL-six and TNF alpha. The problem with this data was that the quality of the data was poor, hence the certainty of evidence that exercise is inflammation modulating is sort of on the low certainty side. But given that there were so many, I think it does speak, to what you've probably been saying to your patients over time, which is, you know, exercise is good for you, exercise will help inflammation. Let's get into some vasculitis, an interesting report from JAMA Network Open, again, about Kawasaki's disease.

I don't know why they're on a Kawasaki's bent over there at JAMA, but this, Japanese study of 106, 101,000 children looked at whether fertility treatments, changed risk of disease. One hundred and one thousand patients, almost one hundred and two. They looked at ovulation induction, intrauterine in vitro, intrauterine insemination, in vitrosemination, and they showed that these fertility treatments increased the risk of Kawasaki disease, significantly, in those who had just spontaneous conception at birth, the risk of Kawasaki's was two seventy four per one hundred thousand patient years. Those who had assisted conception, fertility treatment, three ninety one per one hundred thousand patient years, that's a forty two percent significant increase in risk of Kawasaki's. I present that because I think two or three weeks ago we talked about Kawasaki's and the incidents going down during COVID with restriction in kids and that sort of, and then it went back up after, you know, in more recent years suggesting the influence of environmental triggers, maybe infections on Kawasaki risk.

This says it's not just environmental triggers that could very well be, a hormonal influence as well. So I thought that was a good study. The news this week was, last week was that the EU removed Avacopan from the market, based on the concerns about the ADVOCATE trial and improper data handling, when the drug was developed. It's still on the market in The United States. MedPage today, reported on a study showing registry data that sort of affirms the risk of liver disease with avacopan, also known as tavnio.

So, it was approved in 2021 for ANCA associated vasculitis. This registry study shows when it was used higher rates of LFTs. No liver deaths, no vanishing bile duct syndrome, modest elevations of LFTs, not enough, I think, to take the drug off the market, but again, there are several infractions here and the worrisome vanishing bile duct syndrome, we're waiting to see what the FDA is going to do in The United States. A retrospective study of PMR patients looked at whether PMR patients were treated with an IL-six inhibitor or conventional DMARR. This is a Medicare database, analysis and they had four fifty PMR patients either receiving first time IL-six or first time, conventional DMARDs at one year, the IL-six treated patients had significantly more glucocorticoid discontinuations, twenty eight percent higher or twenty percent more, and they had, an insane twenty eight percent more, significantly more patients who achieved minimal glucocorticoid use, meaning one or two milligrams per day.

It turns out though that if they did get an IL-six inhibitor, there were more hospitalizations and infections that were twofold higher in twelve point two versus five point seven per one hundred patient years. They didn't say that whether those infections were serious infections, but that number looks like it might be, and the risk was seen mainly in the first year but not in the second year of these two different kinds of therapy. I put it up because I don't think, recently we covered the guidelines for the treatment of large vessel vasculitis, GCA, and also PMR, and what drugs you can use when you want a steroid spare per the ULAR guidelines, that was covered a few weeks ago, but I'm of the belief that you and I are probably not using enough steroid sparing therapy in PMR elderly and giving them steroids. Is that really a good idea? It can't be, and if you have FDA approved drugs that work, why not?

Speaking of drugs that work in PMR, secukinumab in PMR was published online back in June and then in paper, I think this week, in the New England Journal. This is a very important study because, it's very well done. It's secukinumab in patients who have refractory polymyalgia rheumatica, three eighty one patients, three treatment groups. There were two doses of secukinumab, three hundred milligrams, one hundred and fifty milligrams and a placebo group. So that's, you know, almost, three eighty patients, followed out to fifty two weeks.

The primary endpoint was sustained remission, no PMR symptoms, and I think being on a successful wean and from week twelve to week fifty two, not easy to achieve. Secukinumab three hundred was forty one percent, secukinumab one hundred fifty, forty one percent, placebo twenty percent. There was a significant lowering of mean glucocorticoid cumulative exposure for secukinumab about, sixteen hundred milligrams in both groups versus, almost two thousand one hundred in the placebo group. So, and this is all interesting because as you know, secukinumab was studied in GCA in a phase two trial called the TITAN study and it looked fabulous. It was the buzz about eight years ago, seven years ago, and then they did a phase three study, which we reported on earlier this year of secukinumab in GCA and it did not meet its primary endpoint.

So it'll be interesting to see how, IL-seventeen inhibitor development goes in PMR. I think there are going to be a number of companies that are working in this area. We can expect maybe future, FDA approved drugs for PMR. Right now, we only have the results of the SAFIRE's data with baricitinib, right? Breplicitinib in dermatomyositis, that is poised for FDA approval in the next few weeks here in The United States.

The results of their large VALOR study was presented in the New England Journal earlier this year, I want to say around April. This week, they had a sub analysis of skin outcomes with repositinib in dermatomyositis patients. You know, the usual myositis outcome measure is the total improvement score, which does not include, skin scores. It includes CPK, global assessments, functional things, but no skin score. So this sub analysis is important.

This is the results of a fifty two week phase three double blind placebo controlled trial, multinational trial, the study was called the VALOR trial that enrolled two forty one adults who had active skin and joint disease and patients were treated with either placebo or breplicitinib, the JAK1TYK2 inhibitor at thirty milligrams a day or fifteen milligrams, I think that's once a day, I could be wrong, and the outcomes, the validated outcomes from Victoria Wurtz Group at Penn is the Cutaneous Dermatomyosis Disease Activity and Severity Index, the SIDACI. The SIDACI A was really important. The SIDACI A clinically meaningful response was also reported. A number of outcomes looked actually very good. The SIDACI A score minus 6.4 versus placebo minus 3.5.

The SIDACI A responders, a higher level thirty three percent versus seventeen percent, itch improved thirty eight percent versus nineteen and a skin related quality of life outcome minus 13 versus minus one. So, that looks good, you know, and I think that this is where maybe brepocitinib, when it gets approved, will hit the ground running, because what are you using to treat patients with really problematic skin disease? You're using methotrexate, you're using steroids, are you using IVIG? I think some are, it is FDA approved, but now you're going to have another option. Lastly, we did a survey this past week on Sjogren's syndrome of you rheumatologists, I want to thank you for answering the survey.

It was a one time email on Monday morning, three eighty three of you answered that email and here are the key takeaways. This is what you think about Sjogren's syndrome. I'm just giving you the summary statements. You want to see the results of the survey, go look at it online. Ninety nine percent of rheumatologists treat Sjogren's syndrome, thank goodness.

Who's the one guy that's not doing it? Let's talk to him. Diagnostic uncertainty is seen in twenty five to thirty seven percent of you and that means criteria for diagnosis and confusion around the time of diagnosis, there still is some concern whether you can make it alone by dry eyes and dry mouth, do you need serologies, do you need minor lip glen biopsies, how important are the autoantibodies, there's still, I think confusion around this and there probably shouldn't be. Diagnostic uncertainty comes up again, same number. The new drugs for these to be used, the main things on your mind about whether they'll be used or not is going to be number one, access, number two, safety, and three, guidelines for use.

Rooms overall are favorably inclined towards using B cell depletion therapies in Sjogren's syndrome. You've probably been using, of you have been using rituximab off label and it doesn't work, it's been proven not to work, I don't know why you would do that, but we do have new drugs on the horizon that will probably approve soon that are B cell depleters. Yanalumab from Novartis is being considered that a successful phase three, Neptunus I and Neptunus II trials that look good, but there is no FDA approved B cell depletion therapy currently, but yet you're encouraged by it. You seem to be, wanting to see the data from the experts and consensus guidelines. You seem to be influenced by disease activity measures when it comes to outcomes in Sjogren's trials.

There's a large educational need for Sjogren's including treatment guidelines, and you claim that about a third of up to, well, ten to thirty three percent of your patients with lupus have Sjogren's and there's little understanding or problem with understanding the pathogenesis of Sjogren's, especially as it relates to the involvement of interferons, and TYK2. Anyway, that's it for this week on the podcast. You take good care of yourself. We'll be here next week.