Don’t Hold the JAK (10.9.2026) Save

It's 10/09/2026. This is the RheumNow podcast. Hi. I'm doctor Jack Cush, executive editor of rheumnow.com. This week on the podcast, steroids are easy to start, hard to stop.

When it comes to vaccination, hold the methotrexate, but not the Jack or biologic. We're gonna weigh in on avacopan and end with age old messages on old age patients. Kind of a cute beginning, don't you think? That's what happens when you use AI. Let's begin with some regulatory announcements.

The FDA has approved the BTK inhibitor from Novartis, Rembrutinib, called Rhapsodyo. It's the first drug approved for dermatographism not controlled by antihistamines. Dermatographism, a key feature in Still's disease by the way. The drug is already approved for chronic spontaneous urticaria. Interesting because we have looked at Rembrutinib in many of our diseases and not had a lot of success in rheumatoid and lupus and whatnot.

BTK's were all the rage a few years ago. It's good to see that they did find a home somewhere. Merck announced its results with its investigational drug in anti TL1A, that's a tumor necrosis factor like ligand 1A. It's an anti inflammatory, pro inflammatory cytokine is an anti inflammatory compound. Theirs is called Tulliso Kibart.

Tulliso Kibart MK7240012. They had a positive clinical trial. Again, all the rage with these TL1A drugs that are in development. This is the next wave, sort of the next TNF inhibitor that'll be used in IBD and derm conditions and rheumatology and rheumatoid. Except so far, you know, not more buzz than actual data.

Anyway, this data on telisocobart phase two showed positive results in moderate to severe hydradenitis at week sixteen, a high SCR50 response of seventy two percent versus thirty five percent in the placebo, that's encouraging. The... That's the good news in, in hidradenitis. There was another one that just recently released, I think it's from Spire Pharmaceuticals, had its TL1A drug that didn't work out quite as well as they had hoped for, and I'm not sure they're going to go forward with that. But there are a number of these in development, you should be looking for them.

Biogen announced its fifty two week data on its amethyst trial. We previously talked about the amethyst trial and the twenty four week data. We had a nice interview with Joe Marola on this. The fifty two week from twenty four weeks to fifty two, they all go into open label. This is a phase twothree study of the plasmacytoid dendritic cell inhibitor, litofilimab, in cutaneous lupus erythematosus patients, ninety three patients.

Between week twenty four and fifty two the results got better, the main outcome being CLA IgA zero to one, that's cutaneous lupus activity by the investigator global assessment of clearing of the skin, and that's cutaneous lupus skin, with either little or no skin. It went like from fourteen percent up to twenty seven percent. And similarly, the classy 70, a high level skin response, also continued to get better, was twenty nine percent at week fifty two. So this is encouraging data. I think we're going down the path of seeing drugs being approved for just cutaneous lupus, and I think that'll be a nice advantage.

Arginx discontinued its phase three trial with efgartimod as a subcutaneous drug, a neonatal receptor antibody knocks down a lot of autoantibodies and immunoglobulin levels and whatnot. It was being tested moderate to severe Sjogren's syndrome. They halted, the Data Safety Monitoring Board, it's called something, Independent Safety Monitoring Committee, was evaluating the continuation of the trial because there were a high number of people that did not meet the primary endpoint at week forty eight of a clinical SDI improvement. And anyway, they affirmed that and the study was discontinued. Whether this gets further evaluation in rheumatic disease, this particular drug from argenx, efgartimod, it's approved for other conditions including myasthenia gravis, etc.

The, one of the company officials, I like their quotes, Sjogren's disease is one of the most heterogeneous and complicated diseases in immunology. I've been saying that for a while. It's hard to get a drug approved in Sjogren's, partly because it's a complicated disease, partly because the assessment of it is really complicated, and there'll be high placebo response rates. Getting a delta above that is going be very difficult. Anyway, that's a sobering piece of news.

Data on rheumatoid arthritis this week came from a retrospective Kuwait registry on RA looking at over two thousand six hundred patients, and they took a particular look at what they called young RA and older RA, or early RA and older RA, or late onset RA. The dividing line being 60 years of age. Eighty eight percent of their patients were 60, and eleven point five percent were late onset RA. And the takeaway from this was that there wasn't a lot of differences between the two groups. Yes, age, yes, disease duration, based on definition alone, but late onset RA had more age related comorbidities, two versus 0.9, but that was mainly related to age and not any other factor when they did their analyses.

But they had similar levels of -twenty eight scores and CDAI scores. The late onset patients had a marginally higher SED rate, forty one versus 33, those are mean values. The bottom line is age should not distinguish how people are going to be treated. Right? Treat the target should be applied regardless of age.

But studies really do show that most of us rheumatologists tend to wimp out a little bit on aggressive therapy in someone over the age of 60, 65 or 70. I don't think there's a good reason for that. And I would implore you not to watch that, and say you're not guilty of that. Another multi center study looked at RA patients, twenty eight hundred sixty five RA patients, who had a mean disease duration of two years that were treated with aggressive biologic or targeted synthetic drugs, including... And then wanted to know what happened to their steroids.

If you gave them all that really tough stuff, that really expensive drug, shouldn't you be able to withdraw steroids? Shouldn't those be steroid sparing therapies? These people were treated with TNF inhibitors, IL-six inhibitors, rituximab, abetacep and JAK inhibitors. At the start of what is relatively early disease, fifty percent were on glucocorticoids, but at three and six months only twenty six percent and thirty seven percent had discontinued their glucocorticoids. Glucocorticoid discontinuations, were more successful with JAK inhibitors than the other drugs.

Not by a lot. Twenty four percent versus seventeen percent. Predictors of not stopping steroids. Being on chronic steroids, having hypertension, that's kind of interesting. Patients treated with TNF inhibitors and abatacept, and rituximab were more likely to stay on steroids compared to the Jacks who are marginally better at getting off steroids.

Something we probably should work at. Steroids are necessary, but they're acutely wonderful, chronically dangerous, are they not? We're in an era now of CAR T cell craziness and cellular depletion therapies, which includes all kinds of NK CAR Ts, allogenic CAR Ts, off the shelf CAR Ts, but there's these other drugs that are the B cell engagers, T cell engagers, BiTEs and TRITES. A report from last month looked at the t cell engager blinatumomab. This is a CD3 and CD19 t cell engager that's used for deep B cell depletion.

It was given to fifteen patients with resistant RA, multi drug resistant RA, and at week twelve, nine out of fifteen had a C. DiffeileDA response. Only three out of fifteen were in C. Diffeile remission. This is a little bit like the CAR T cell therapy it was reported at EULAR.

It showed success, but it wasn't that great, you know. It wasn't nothing to, you know, to go out and, put all your patients on it. They did show, based on biopsies, good B cell depletion in four out of five biopsies of tissue, but not in the lymph nodes. And then later, fourteen out of these fifteen patients did flare. The good news is, not much in the way of toxicity.

There were no ICANS reports. There were three out of fifteen patients with cytokine release syndrome, grade one, not too bad. There was one death a year after therapy, probably unrelated to this. So anyway, we're going to see more on these cellular depletion therapies, including the T cell engagers, B cell engagers, BiTEs, TRITs, etc. A meta analysis of IVIG in scleroderma.

You know, I've never used IVIG in scleroderma. And this report surprised me, because 11 studies, three sixty three patients showed IVIG was safe, that I would have expected. But across the board it showed a significant improvement in modified Rodden's skin scores. It not only improved skin, but it also improved GI manifestations in a significant way. And those people who had inflammatory myopathy also had a significant reduction in creatinine kinase levels.

Something to consider, you know, I think that we are mounting some evidence that some therapies... We don't have great studies, right? But some of the therapies that we are using can have efficacy in systemic sclerosis patients. We have a bunch of reports on vasculitis and a few reports on avacopan. Let's start with discussion of a Danish national study of 51,000 PMR patients.

Half managed by primary care, half managed by secondary care MDs, I assume that's rheumatologists. The incidence of PMR is one hundred and twelve cases per one hundred thousand. That seems to be on par. But the incidence over time, they did this between, over the years, ten year interval between them, but the incidence of PMR in primary care went down but increased in secondary care. I'm not sure why that was.

Overall, there was a decrease in number of PMR cases. The interesting thing here, remember the incidence rate is one hundred and twelve or one hundred thousand. Those PMR patients, how many of them develop GCA? You know, always talk about, should you look for GCA in PMR? I don't.

It should be obvious when they have it. I'm not gonna go searching for it in everyone. I think that's not cost effective. The rate that they found was five per one thousand patient years. That would be...

Times 10, that would be fifty. That says half of them? I think I might have that wrong. I think that's five per one hundred thousand patient years. I think the bottom line was it's not many patients, and it developed within sixty eight days of a PMR diagnosis.

The bad news from this study though, that I am certain about, is that after five and ten years these PMR patients were still on prednisone either twenty eight percent at five years and twenty two percent at ten years. Hence the line oh I'm only going to give you prednisone for two years and you'll be off of it is not true. You know, more realistic is five years you gotta work hard at getting them off of that. An Italian study looked at secukinumab in difficult to treat GCA patients. There's only thirty six patients.

And you know there is the story of secukinumab in GCA was that the TITAN study from five six years ago was a very positive phase two trial, but the phase three trial, the GCA CAPTAIN study, showed didn't work that secukinumab failed to meet its primary endpoint. But then conversely Novartis reported that when secukinumab was used in PMR recently in a phase three, that looked good. So here's a small, uncontrolled, 36 patient, difficult GCA, and they were given this drug because they either had relapsing disease (seventy two percent of them previously received tocilizumab), they basically showed clinical remission at eighty five percent at three months and eighty three percent at twelve months. GCA, I'm sorry, steroid free remission was achieved in twenty eight percent at twelve months. Forty three percent were able to discontinue their steroids.

So this is uncontrolled, you know, and this is at odds with this other phase three GCA Captain or the GC Captain study... You have to look at the mnemonic, it's goofy. Wonder whether this is going to be legs here or not. I do think we're going to see IL-seventeen inhibition in PMR. I don't know about in GCA.

But I certainly would like to see it. I think we need more options of steroids bearing therapy. I often teach that GCA is a condition of old white people. And, you know, I worked at VA clinic where it's old white mostly males and some females. A lot a lot of, GCA.

In my university practice at the university, a lot of Caucasian older people, a lot of GCA. At Parkland, the county hospital, a lot of Hispanics and a lot of African Americans, very rare to see GCA. But everyone argues with me when I say... When they say, no. No.

You can have it in in non whites. Well, here's a report coming out of Martinique of forty three biopsy proven GCA patients from The Caribbean. And these are... You know, Caribbean blacks are often very mixed race, but these are labeled as Caribbean blacks. The incidence rate was one point seven six per one hundred thousand.

That's about half the rate that you see in Caucasians of Northern European ancestry, three to four per one hundred thousand. But they did see in from 1993 to 2014 a fourfold increase in reported cases. They were old 76. They were more female four to one female to male. They are presenting features sixty five percent headache, jaw claudication thirty three percent, scalp tenderness thirty seven percent, anterior ischemic optic neuropathy twenty six percent, and PMR was seen in a third of the patients.

The mean survival of these people, again, they're older people, mean age 76, was 13 years. So it's slightly different, but, you know, it happens. And if you suspect it in a non white that's elderly, do the biopsy because that's the only way you're going to prove the diagnosis. Two reports on avacopan. As you know, avacopan was removed from the market in Europe by the EMA over safety concerns and inappropriate reporting and a rare, you know, event that affects the liver.

And it's up for review by the FDA. I think the FDA is waiting to see more reports in the literature like these two reports I'm going to tell you, and there's a bunch of reports at ACR that are upcoming that I'm reading the abstracts on right now. Most of these reports are actually not damning and not indictful and may not support removal from the market in The United States. So here's a retrospective real world report from a UK vasculitis center that looked at ANCA associated vasculitis patients who were treated with either cytotoxin cyclophosphamide or rituximab, and one hundred and thirty three of them received avacopan four fifty eight did not. At one year the avacopan patients had a non significant increase two fold increase in ALT that wasn't that much different between the avacopan plus and the avacopan minus 16% versus eleven percent.

That was not significant. If you looked at three fold elevations of ALT, it got a little closer significance, but still not significant. 11% versus 6%, p value 0.064. No difference in other liver enzymes. Alk phos, bilirubin, and patients on avacopan were less likely to meet High's law, which means that there's a ten percent chance of death from liver cause.

It was low between both groups. So, that's encouraging information. Another retrospective study looked at three eighty seven ANCA associated vasculitis patients on glucocorticoids, on immunosuppressants, and they either got avacopan or not. Fifty two avacopans versus three thirty five non avacopan. Now both these studies, they don't tell you why they're on avacopan.

So, there's a channeling bias in some of these reports. Right? But I would think if they go on avacopan, it's either because they're worried about steroids or because are... Patients have more aggressive disease. But anyway, you know, there's no clear indication as to why someone goes on avacopan in either of these cohorts or not.

Anyway, in this cohort of three eighty seven AAV patients, avacopan was associated with less severe, infections, with about a seventy eight percent significant reduction at one year. And that was because they used less steroids. And if you looked at those on avacopan, non avacopan, no difference in relapse rates. Again, I think that's encouraging data. Two reports on Still's.

A study of sixty four patients looked at macrophage activation syndrome in Still's disease. Fifty five of these were systemic JIAs, nine were adult Still's. They were all treated with glucocorticoids. Seventy five percent received anakinra, fifty two percent half of them received cyclosporine. Complete remission of the sixty four was seen in only seven patients.

Partial remission was seen in sixty four percent of the sixty four patients. Steroids were tapered in seventy eight percent in a median of forty days. The bad news, the good news is that the one year survival probability of these Still's disease related MAS patients was ninety three percent. That's good news. The bad news is MAS recurred thirty one percent of the time and eleven percent died.

Now that's better than some other reports of MAS in kids or adults with Still's, where the number can be as high as thirty nine percent mortality rate. This is a serious and bad complication of Still's identification aggressive treatment. They only looked at anakinra. There's a lot of other drugs including emapalumab, the gamma interferon monoclonal antibody inhibitor, that is very very effective and has recently been FDA approved. Another report looked at a potential biomarker in STILS, and that's looking at serum anti IL-1Ra levels.

This was studied in forty six adult STILS patients that were not previously treated with anakinra, which as you know is an IL-1Ra inhibitor. And they found that IL-1Ra levels were significantly higher in stills versus controls, but they did not differ between active and inactive stills. Hence, it's not going to be a good biomarker. But if you looked at what they and they don't have a great definition by the way of inactive versus active stills. It's kind of up to the investigator, right?

But the inactive patients had no rash, no fever, but they had occasional lymphadenopathy, hepatomegaly, they had occasional elevations of ferritin, you know, so it's... There's no difference in IL-1Ra levels, inactive and active. I don't know that that's going to hold up in a court of law, but, I know you're really interested in Still's disease like I am. A New England Journal report this week looked at retreutide. Retreutide is a new investigational incretin GLP-one like agent.

This is a triple receptor agonist therapy that targets GIP, GLP-one, and glucagon receptors. It's thought to be maybe better, maybe better GI tolerated, maybe better at weight loss. And in this study of... Oh, a few thousand people, I think, 2,000 people, a lot of people, the highest dose of this drug was associated with 25% weight loss. That is superior to tirzepatide and semaglutide in this study.

But what's interesting about this study, and again, they gave this drug retrutide at either four milligrams, nine milligrams, or twelve milligrams once a week, or placebo. The end of study is eighty weeks. The study did include five seventy four patients with moderate to severe osteoarthritis with radiographic evidence of OA, and two forty three people with sleep apnea. Of the five seventy four with OA, Womack pain scores were significantly better with the new triple receptor agonist drug, retreotide, compared to placebo. Roughly about 3.5 versus minus 1.9 drop in Womack scores.

Similarly, the sleep apnea was improved on the incretin therapy versus placebo. This is going to be on the market. It's not yet on the market, but it's going to be on the market. And I think there's another report on this at ACR that you'll be hearing about. Last is a report, just published in JAMA from Jeff Curtis and colleagues that looked at What do you do in patients who are going to get COVID vaccination or boosters of COVID vaccination?

Should you hold, the biologic or the JAK inhibitor? We do know in very well done studies with influenza and some studies with JAKs that you want to hold methotrexate for one or two weeks, I like one week, and it won't impair, the vaccine responses. If you're on methotrexate, it will impair vaccine responses. But if you hold it for a week or two the vaccine responses are as you'd expect and there's no flare with methotrexate. What happens in the case of now, they're studying COVID vaccination, revaccination, with what do you do with the JAK or the biologic?

So in this study, they tested whether you, should hold either the biologic or the JAK inhibitor for two weeks. They showed in a study of eight forty patients with inflammatory arthritis, and that included, RA, PSA, axial spondyloarthritis patients, they showed that holding the biologic or the jack did not impair vaccine humoral responses. So that seemed like it was a good thing to do. But it did increase flare risk, with a two fold odds ratio of two point two seven increase in flare risk, mostly seen when you held the JAK inhibitor, which would be the short acting of all the drugs being used. So, I think that the bottom line is I still would hold, a JAK inhibitor for a week.

I don't know about a long acting biologic, you know, like an IL-seventeen inhibitor or a TNF inhibitor, it doesn't seem to make much sense. Holding it for a week does very little, if you will, because they have such long half lives. But I think this is important to look at, especially Jack inhibitors and how that should be handled. Anyway, that's it for this week on the podcast. By the way, registration for RheumNow Live is open.

We're posting the agenda and speakers next week. I think you're gonna like the program. I'm really excited about it. You will be too. Tune in next week.

Thanks.