Doubting RS3PE (8.14.2026) Save

Hello everyone. It's August 14, 2026. This is the RheumNow podcast and I'm Dr. Jack Cush, executive editor of RheumNow.com. This week on the podcast, cancer, deadly viruses, AI. Oh, more AI rules. But there's going to be some poetry and good moon rising.

Let's begin with numbers in medicine. A report this week in JAMA talked about the number of internal medicine doctors that have dropped in the United States. I think the purpose of the article was to point out the consequences of recent immigration policies which are hurting healthcare. They looked at the 2026 PGY1 match rates and showed that the number of non-US citizens who are international medical graduates has reached a 5-year low. But say what you will, think what you might, the fact is that international medical graduates in most instances make up as much as a third of our healthcare delivery. We need them as much as they need us.

Buried in there were some interesting numbers for rheumatologists. It's always a bit of a puzzle as to how many rheumatologists are there in the United States. The ACR has numbers. They recently crested over 6,000 in their last release. In this report that looked at NPI and Medicare numbers, the number of rheumatologists in the United States is 6,300. How many of those are born locally or born internationally or where were they trained? The greatest majority, 47%, were US-born, US-trained physicians. The next biggest lot is 37% were foreign-born, foreign-trained physicians. I am a US-born international medical graduate. I graduated from St. George's University in Grenada. We only make up 5% of the rheumatology workforce. And then non-US-born, foreign-born, but trained in the United States is 11%. I think you belong to one of those groups. We all belong to the same group, the great group of rheumatologists.

A biomarker substudy — as you know, is an interventional trial used for registration of nintedanib for patients with systemic sclerosis-associated ILD. This looked at the biomarker studies that they did. They looked at a number of different things. The two things that stood out in this substudy was the biomarker that's used all the time in pulmonary medicine, KL-6 — and is that KL-6 or KL-5? You look it up. Levels greater than a thousand at baseline was associated with greater risk and worsening of FVC, meaning you're at a higher risk category, you're more likely to progress and progress more rapidly. The other interesting thing I didn't know about was CA-125, used in other contexts as a cancer biomarker, showed that a decrease in CA-125 as a result of treatment especially was associated with better responses to the study drug, which was nintedanib. We do know that CA-125 is produced in the lung. You may want to consider doing these biomarkers in your patients in whom you worry about ILD. And I don't think it just applies only to scleroderma-associated.

The Japanese put out a study this week looking at five predictive factors for cancer-associated myositis. They had a cohort of 364 patients meeting IIM criteria. 11% of them, or 42, had cancer-associated myositis, abbreviated CAM. 30 of the 42 were diagnosed within one year of the diagnosis of myositis. And generally it's been said that the risk of cancer is 3 years around the diagnosis — plus or minus, before or after — a myositis diagnosis. But they showed in their study that the risk is highest in the first year, with an SIR of 8.6, and is still high at 3 years at 2.5.

The point of the study was how can you predict? There were five predictive factors: TIF1-gamma, elevated CRP, dermatomyositis, older age, and a positive family history of cancer. Using those five, the AUC was 0.86, sensitivity 92.5%, and specificity 65%. These are pretty good. We talked about the IMACS risk stratification, I think two or three podcasts ago. I think this sort of complements that, especially who might be at high risk. And I like that these can easily be employed into practice. But I do want to say, of those five factors, there's a disproportionate dominance of TIF1-gamma. TIF1-gamma antibodies — if you look at the bar graph — was way out there to the right compared to everything else. So again, myositis-associated testing for antibodies I think is indicated, especially in older patients, especially in dermatomyositis.

Speaking of odd tests, anti-Ku antibodies — the good news is I can spell it, K-U. The bad news is I've never ordered it because I've never seen the point. But the point of this paper was a study of 154 anti-Ku antibody-positive individuals showed some interesting data. First off, one-third of them were from myositis patients. And it is a myositis-associated antibody. It is not a myositis-specific antibody. But 46 had lupus, 30 had Sjögren's, and 27 had scleroderma. 39% of these Ku-positive patients had ILD, and those people with Ku were
more likely to progress. 75% of them had progression, especially in males. So could anti-Ku antibody, regardless of diagnosis, be a marker for that? Maybe you should order it. And unlike me — I was about to write that because that was a takeaway of the paper — and then I started playing on open evidence and looking for what's the story on Ku. But Ku is rare, rare, rare. Even in myositis it's less than 4%, you know, it's 1 to 4%. It's not specific, as this paper says. It's seen in almost as many people with lupus as there is with myositis. It doesn't have clear clinical implications, although that's what this paper would want you to believe. And there are other myositis-associated antibodies that you don't often order in myositis, like Ro 52, Ro 60, U1 RNP, and PM-Scl. Another test I've never ordered. Maybe it got ordered inadvertently. The point is, this is interesting data. I don't think it's going to change my practice.

What do you think? The CDC put out a report this week. Actually, my editor found a report on Medscape which references the CDC, released this week, saying that patients treated with anti-CD20 monoclonal antibodies are at a higher risk for severe arboviral disorders — arboviral infections, especially those that affect the neurologic system — and that there is a 40% risk of death. There's a high risk of serious neurologic sequelae, and we use anti-CD20 — do we not? — rituximab, ocrelizumab, just recently approved. These are in that category.

Now, what I don't like about it: first off, the most common arboviral infection noted was West Nile virus. The other ones were so uncommon they don't even list them, but there are a number of, you know, eastern equine encephalitis virus — you don't see that often — but arboviruses are alphaviruses. I think that includes the viruses that cause chikungunya and Zika and other things. And we do know that B cell inhibition, especially monoclonal antibody B cell inhibition, is associated with more viral infections, including herpes zoster. Rituximab is associated with PJP infections — that's not a virus, that's a fungus. But the point is that if you're going to use B cell inhibition, there is a risk of serious infections, some of which may not be overt bacterial infections. So you want to be aware of this and watch for this.

The other thing about that CDC report: they don't give any numbers. You know, tell me this was 3,000 people in Wisconsin and I'd be worried. But there are no numbers, and there's no numbers on mortality rates or hospitalization rates. Maybe that'll get fleshed out in the future, but at this point it's just a warning that's designed to scare rather than instruct. And of course, I'm reporting it — I'm part of the problem.

A study this week on glucocorticoids and depression. You know, I don't know about you, but when I prescribe steroids to my patients, my objective is primarily to treat the patient and what's urgent — so much so they need a steroid. My other, very close second objective is to scare the hell out of them about steroids. I'm going to give you this drug, it's going to make you feel wonderful. Steroids are the best drug and the worst drug. Worst drug? What do you mean? Yes, if you stay on steroids, you're going to get fat, you're going to get ugly, you're going to get hypertensive, you're going to get diabetic, you're going to get cataracts, you're going to get muscle weakness, you're going to get stretch marks, you're going to have a higher risk of infections — and I mean mild infections, serious infections, hospitalizable infections, kill-you infections — and you'll have a higher death rate. And of course, the patient at this point is like, whoa, whoa, whoa, Cush, what are you doing to me? Well, that's what I've done. I've now motivated them to get off of steroids.

Well, this interesting study — and we always talk about the CNS side effects of steroids. I think we talk about steroid psychosis a little too much. I rarely — maybe I've seen one really good steroid psychosis. It does play games with the head. Mania is way more common. If you have an underlying psychiatric problem, psychological problem, that'll get worse. But is there an association with depression? And clearly I think there is. This UK Clinical Practice Research Database study of 3,100 people on steroids who have depression in that large UK database — 3,100 of them were on steroids. They matched them against other patients who were not on steroids. So glucocorticoid use was associated with a significantly higher risk of starting an SSRI antidepressant drug. That's kind of interesting — sort of fortifies the association. This applies to starting a recent glucocorticoid, where the odds went up 53%, or previously, or in the past, you've been on a glucocorticoid, where the odds
go up 40%. Those are significant. So is this depression that's linked to the disease — having pain and severe disease and chronic disease gives you more depression — or is this depression linked to therapy for depression linked to the use of the glucocorticoid? Yes and yes and yes, we should be worried about depression in our patients.

Another study from NHANES looked at the prevalence of arthritis in adults who have depression. So these are 15,000 depressed patients with a PHQ-9 score of greater than 10. Of those people that had arthritis, RA was most prevalent. And when they looked at this NHANES from 2005 to 2018, a 13-year period, the RA prevalence went up in depressed patients from 7.8% to almost 18%. Interestingly, psoriatic arthritis, unknown association with depression, declined from 7.2 to 1.7 and OA remained unchanged at about 10 or 11% over this span having depression if they had OA. So in the end the risk of depression was highest with RA — 40% higher, 44% higher with psoriatic arthritis. So the association with psoriatic arthritis is real but maybe the heightened awareness of that has led to better treatment, or I'm not sure exactly what, but I like that the numbers did go down.

Again, PHQ-9 was the identifier in this study. There's also a PHQ-2. These are either a nine-question survey test or a two-question PHQ-2 that you can incorporate into your survey or in your patient intake so you can identify patients who have depression and then manage that.

Pollution was in the news. A Korean study showed that RA activity and flares is increased by pollution. A thousand patients, I think this was on POS1, were assessed for disease activity in their RA and they looked at pollutants that were prevalent in the era and the location of the patient. We're talking about sulfur dioxide, nitrous oxide, ozone, carbon monoxide, particulate matter 10 — that's 10 microns or up to 10 microns — or particulate matter 2.5, PM2.5. So amongst these pollutants, PM2.5 had the greatest risk of flare — 11% increased risk of flare if they're exposed to particulate matter — and also increases in DAS-28, CRP, CDAI, TJC, and SJC. This was seen more so in women who were non-smokers.

So again, I made that one of my program lectures in past RheumNow Live lectures, and you know, it's a really hot topic — environmental rheumatology. What are the things that surround us besides diet, which affects the microbiome, and smoking, which affects the lungs, and pollution — and probably there are others that we are not yet focusing on, because these become modifiable risk factors, do they not.

Did I mention RheumNow Live? Oh yeah, it's coming January 30th and 31st in Dallas — a day and a half meeting, the best meeting in rheumatology, the most interactive meeting in rheumatology. You can register now for RheumNow Live.

The POETYK PsA-1 study — it's also sometimes called the POET study because no one can pronounce POETYK, which ends with a T-Y-K. This was the registration trial that got deucravacitinib approved. It's a trial in biologic-naive PsA patients with active disease. 670 patients were randomized to receive deucravacitinib, a selective oral TYK2 inhibitor, and the patients with PsA did really very well with ACR20, ACR50, ACR70 and other measures as well. The ACR20 response was 54% versus a 34% placebo response — a delta of 20% — that is significant in this day and age, and that higher placebo response is significant in this day and age for reasons that we've already discussed. Again, these were biologic-naive PsA patients who had erosive disease. The other readout on this was radiographic benefit, and deucravacitinib, a TYK2 inhibitor, was shown to inhibit x-ray progression in these patients both at week 16, very early, and at the longer endpoint, week 52.

Good data finally published — we've talked about it for almost two years on RheumNow. New data coming from MoonLake — that's a good moon reference right there — and they announced their phase three data of their IZAR-1 studies. It's a randomized controlled trial of sonelokimab, their dual IL-17A/F inhibitor that's not yet approved for PsA, but this trial showed significant responses at week 16: an ACR20 of 66%, an ACR50 of 42%, an MDA of 41%, a PsA90 of 61%. These are all very favorable data. There is a phase 2 IZAR-2 trial that's in progress. I would expect to see another dual A/F inhibitor on the market sometime in the future.

A sub-study of 131 patients from the AIDA registry — that's the Auto-Inflammatory Disease Alliance registry — looked at responses to canakinumab. In that 131 patients with Still's disease, kids and adults, 38% were underdosed according to the package insert, 62% were appropriately dosed, and not surprisingly the underdosed patients had a lower odds of achieving remission or being able to discontinue canakinumab in the future.
Discontinuation of canakinumab — meaning that they went into remission, you no longer need the drug. So discontinuation was 3.9% overall in the underdosed and 19% in those that were appropriately dosed. I want to remind you, if you're treating Still's disease, you may have a dose in mind for an IL-6 inhibitor or an IL-1 inhibitor, but look up the data or look up what I've said about this in the past. Sometimes you need more than the usual dose. 100 milligrams of anakinra may not be enough. 300 milligrams of canakinumab may not be enough. 4 to 8 mg per kilogram of tocilizumab is definitely not enough. In the TENDER trials for systemic JIA they used up to 12 mg per kilogram. The point is, at the outset when they're red-hot in the hospital, in the ICU, crazy scary labs — don't be afraid to go a little high. Get control of the disease, have some background steroid, and then wean down the therapy.

Speaking of scary diseases, a Kawasaki disease report becomes instructive this week from Japan, looking at the incidence of Kawasaki from 1975 to 2025. A 16-fold increase. Whoa. In 2023 and 2024, they roughly had about 15,000 cases annually of Kawasaki disease in Japan. But a big part of this report was that the number of Kawasaki patients dropped significantly during COVID, and even after COVID it was still 10,000 in 2022 — much lower in 2020 and 2021 — but it rebounded post-COVID when all the restrictions on kid exposure, from masking to being out of school, etc., lifted. Infants and infant rates did not change during COVID, but kids 5 to 9, school-age kids, showed the greatest increase. The point being here that this is probably a communicable, infection-related, or airborne-related phenomenon, or at least in part is, and this should help researchers who are working on this.

We put up a report from JAMA this week with updated guidance — these are JAMA rules on the use of AI. They cite that despite increasing use of AI in society by everyone, including you, me, and your mother who still doesn't know how to operate a VCR — who has a VCR — in the journal world, the medical literature world, AI disclosure is rarely noted in the methods or in the paper. There's a bit of a problem here. We note it in RheumNow. There's a checkbox, and I and my team use a lot of AI. We use AI for research, organization, first drafts — and then we disclose it, and you'll see that when you look at the disclosures on things that I write or appear in RheumNow.

Here are the new rules for AI in JAMA. AI must not be used to generate references. If you've ever looked at references generated by AI, it's funny — they're not even close. Do references the right way. AI cannot and should not be used to generate opinion articles, letters to the editor, or online comments. How lazy are you? You're not even writing a real full-length paper — you're writing a letter to the editor and you're using AI. Come on. Clinical images, illustrations, and AI-generated video or audio should not be used unless necessary for the kind of research you're doing. Disclosure is mandatory and must be placed in the acknowledgements, if not other areas, but at least in the acknowledgements and methods sections. And the other one that I found really surprising and new is people using AI to review articles. So I get invited by the journal of irreproducible results to review an article that I wrote anonymously on Still's disease, and it gets sent to me to review — but I'm too lazy, so I take the article and put it into Claude or Gemini or Copilot or ChatGPT. And really, people are doing that. Again, it's lazy. It's prohibited. If they catch you doing it, they're going to hang you up by your thumbs.

Two more reports. The ZEUS trial is a cardiology trial that's got nothing to do with rheumatology, but it's got everything to do with the concept that cardiologists have been playing with — that inhibition of inflammation will lead to better cardiovascular outcomes. They have an IL-6 inhibitor, ziltivekimab, and they did a phase three trial of over 6,000 patients who were high risk: they had atherosclerotic cardiovascular disease and CKD and an elevated high-sensitivity CRP. Hence, the population was enriched for people who would likely have an elevated CRP and likely benefit from IL-6 inhibition. And guess what? IL-6 inhibition dramatically lowered IL-6 levels and lowered CRP levels, but didn't change cardiovascular outcomes. All-cause mortality did not improve — hazard ratio 0.99 — even in a highly enriched population. There was no change in MI, stroke, or cardiovascular death.

Now this follows on the heels of other well-known trials: the CIRT trial with methotrexate, the CANTOS trial with canakinumab and IL-1 inhibition, and two colchicine trials that have basically shown — well, the colchicine trials did show benefit, but the IL-1 and the IL-6
inhibition trials did not show benefits in seronegative and methotrexate. So again, I think this is data that you need to know about. It's great maybe to lower acute phase reactants in heart failure, but they're going to have to do other things and do the things that they typically do.

An article written this week by Lee and Morris and co-workers was a review article from late June in JAMA on evaluating inflammatory joint pain in older adults. Really popular, got tons of reads. The takeaways here are that there's a significant diagnostic delay in the elderly. That should not happen, but it may happen because of atypical presentations or symptoms being ascribed to, oh, you're just old, it's aging, get over it. Or problems with labs. They want you to know that seronegative RA can mimic PMR and vice versa, and that you can distinguish between the two based on hand and tenosynovitis and elevated inflammatory markers, and that dysfunction favors RA over PMR. They want you to think about mimics here that could be misdiagnosed, including CPPD, inflammatory OA, and RS3PE. Let me come back to that in a second.

There is a lot of suspicion and worry and inaccuracy about laboratory testing in the elderly. They have a three-fold higher rate of autoantibodies — ANA, rheumatoid factor, and CCP. Sed rate and CRP are falsely elevated by age, especially sed rate, where the formula is: your sed rate upper limit should be your age divided by two if you're male; if you're female, it's your age plus 10 divided by two. So an 80-year-old woman — plus 10, that's 90 — the upper limit is 45. So that's not elevated for an 80-year-old woman. And they want you to use other diagnostic tests like ultrasound, not just radiography, especially if you are suspecting this.

Lastly, the big point is the elderly are undertreated when it comes to DMARDs. Age should not be a contraindication to methotrexate use or biologic use, but yet all studies show it is — you seem to have a hesitancy because maybe they have comorbidities. Well, comorbidities are prevalent all the time and not just restricted to age.

Let me say something about RS3PE. I have never seen one. I joked about this back when Dan McCarty wrote about it during my fellowship. Not that I was joking about Dan McCarty — a giant. I worship the ground he walked on. But he described this seronegative symmetric synovitis with pitting edema, RS3PE, as a unique syndrome, possibly crystal related. But honestly nobody knows what it is. I don't think you've ever seen it. I think if you follow them long enough they become something else. There is no epidemiology on this. I did some research because I want to fortify my being a curmudgeon on this. There are no numbers on this. Even with the most rare disorders, I can give you the exact epidemiology on Still's disease. There are no numbers on this, but it's rare. They don't even say it's very rare. If I've never seen it, it's very, very rare. And hence I'm not even sure that I know what it is, except in this article they say if you diagnose RS3PE, recent reports suggest that you should be thinking about an occult malignancy.

So we don't know the cause. It could be some crazy variant of RA, which is probably 39 disorders, not one — seropositive, seronegative. It's been described with immune checkpoint inhibitor-related adverse events. It's got linkage to HLA-B27 and HLA-A2. So despite my protestations, there's still a science here that's unresolved. I don't know. I just want to be a good rheumatologist.

So let me end with that. A great quote — one of my favorite quotes — from the comedian Steve Martin, as he was coming up in the business: "Be so good they can't ignore you." I like that. Be so good they can't ignore you. It means there are no shortcuts to greatness. That applies to your career, your family, the people you work with, your group. And why not your patients? Be so good with your patients that they have to say, "Oh yeah, I have the best rheumatologist in the whole world." God bless you and God bless rheumatologists.