Treating Obesity is Disease-Modifying (9.4.2026) Save

It's 09/04/2026. This is the RheumNow podcast. Hi. I'm doctor Jack Cush, executive editor of rheumnow.com. This week on the podcast, drugs being approved, new drugs put on hold, and drug use out of control.

This week and more. Let's begin with an FDA approval. It came about one week ago today. The FDA approved the, indication for dermatomyositis with the new novel TYK2 JAK1 inhibitor, Brepocitinib. This drug has been in development for a while.

The approval is based on a large phase three VALOR study, two forty one patients with dermatomyositis treated for fifty two weeks, showing against placebo significant benefits for both skin, motor, and functional outcomes. The drug gets approved as a single, once a day oral, Tic JAK inhibitor. Brepocitinib has a mean, terminal half life of five to twelve hours. The drug dose is thirty milligrams once a day with or without food. It does come with the same box warning that you see with the other JAK inhibitors, right?

Worries about MACE, malignancy, serious infection. As you'd expect with new drugs of this type, not surprising, patients should be screened per the package insert, screened for latent TB and viral hepatitis, have a CBC, LFTs, and renal function tests. There are warnings for GI perforations presumably because of the IL-six inhibiting potential of the drug. I don't think they've had problems with, GI perforations. Similarly, hypoglycemia, abnormalities of lymphocytes, neutrophils, hemoglobin, LFTs, and they recommend this drug not be used with other immunosuppressive and not, patients should not receive live vaccines, and patients who have either, renal impairment, severe renal impairment, liver impairment, or pregnancy, planned pregnancy should not go on this drug.

There have been reports of viral reactivation including, herpes zoster virus cases in patients taking this in clinical trials. So, it's a welcome addition to autoimmune disease that has very few FDA approved options. You know, IVIG, I guess, would be the only one that truly is FDA approved, and we do know there are other drugs that are being developed in this area. So, this is a welcome change. The other big news this week was, the announcement that both Novartis and BMS stopped their CD19 CAR T cell therapy trials temporarily.

The Novartis trial was put on hold because of concerns about on three deaths with their CAR T cell called RAP cell. They had three deaths related to, basically, a hemophagocytic syndrome related phenomenon. This led to them halting their trials, looking at their data. They have eight clinical trials in autoimmune disease and in neurologic disorders, two neurologic disorders, six autoimmune trials that are on hold pending an analysis of their data and discussions with the FDA and other regulatory agencies. BMS is a different story.

They had no deaths. They had actually, suspended their trials a little while ago, but it just got announced at the same time as these folks because they had noted, the occurrence of what they call transient and reversible inflammatory events with their CD19 CAR T cell therapy called ZolaCell, BMS-nine hundred eighty six thousand three hundred fifty three. Through an abundance of caution, they're doing an analysis. They, said that their, observed side effects are in line with that expected for CAR T cells and they expect to resume, their trials soon. Novartis provided no information about when their trials would be resumed.

A lot of CAR T cell studies are in development. I guess this is putting everyone on notice to take a doubly good look at your safety. Another drug that's getting a lot of buzz are the obesity drugs. You may have noticed this month, September, is an obesity month. We have a big obesity campaign going on.

We're gonna have a lot of good education about obesity and, how it affects rheumatic disease in autoimmune patients. New York Times reported recently, the results of a Gallup poll that shows a significant increase in the number of Americans who are taking weight loss drugs. In that poll, fifteen percent of those surveyed said they had taken a weight loss drug and eleven percent of them were currently taking and that's up, in, I guess, a year and a half from three percent to eleven percent or to fifteen percent. That's a lot of people taking weight loss drugs. These, drugs as you know, the GLP-one related drugs or combination drugs have been approved for not only type two diabetes, but also for weight loss, obesity, liver disease, NASH or MASLD, those who need a significant reduction in cardiovascular risk, and also for sleep apnea.

You know, I've counseled a number of patients recently who had significant problems with fatigue and headaches and numbness and basically fibromyalgia because they had bad sleep apnea and they're still, they are on CPAP, but their sleep is still not controlled. Well, other than fixing their CPAP and getting on other meds to improve their sleep, this is another consideration that should be talked about with their doctors. Another diabetes related drugs, is the class of SGL-two inhibitors, which are shown to be, as we mentioned last month, very effective in gout. A retrospective study looked at, type two diabetics, over half million of them treated with an SGL-two inhibitor versus, one point five million treated with sulfonylurea, and they showed that the SGL-two inhibitors had an eleven percent lower risk of developing autoimmune rheumatic disease, including inflammatory arthritis. Hazard ratio of 0.89 and that was significant.

So, when you look this issue up, it's a little bit of a mixed bag, but in general, it's quite positive that SGL-two inhibitors are both good for the diabetes, may have cardiovascular benefits like GLP-1s, but also may reduce the risk of developing disease, may not necessarily control the disease. That's where things get a little dicey. But I think this is great new evidence, especially in our patients who have a significant amount of comorbidity, do they not? Let's talk about lupus. New England Journal published an image and case this week of a lupus patient with what looked like severe deforming arthritis, but it was Jacuzzi's arthropathy, and I think it was a 40 year old woman.

And I put it up because it's a reminder, it'll show you a good video of a horrible deformed hand that when the patient makes a fist, the deformity all goes away. Patient had, I think, swan necks and what looked like subluxations. Jacuzzi's arthropathy is a chronic deforming arthropathy that results from laxity of ligaments and tendons, not damage. So, you know, when you do x rays, the x rays are normal, there's no erosions, and their function is actually quite preserved. Jakuds can look like and mimic RA but it's more likely to be seen and associated with lupus.

A study of a fairly large 4,000 patient cohort with lupus looked at the neutrophil to lymphocyte ratio, the NLR, was actually a meta analysis of four thirty one studies, and showing that NLRs were higher with active, versus inactive lupus and showed a moderate correlation with sleep eye. The great thing about an NLR is it's free. It's cheap. You're already collecting CBC data. It's the neutrophil divided by the lymphocyte and it's that ratio.

You know, if it's less than three, it's probably okay. If it's higher than three, there's an inflammatory state that's in play. If it's greater than six, uh-oh, you know, call the mounted police if you're in Canada. It's it's a really good and I don't know why when your CBC reports, we should be lobbying to get the CBC to automatically give us an NLR. You know, there's a platelet to lymphocyte ratio and a few other, you know, cellular comparison ratios that have predictive value.

But the NLR is consistently predictive in almost every disease that's been looked at. It's a very good, very cheap inflammatory tool. A VA study looked at, their VA patients who had RA and how many of them got cancer and they found a significant association between frailty. So, they measure frailty in two thousand seven hundred RA patients and looked at the future risk of cancer, and the cancer rates per 1,000 patient years were twelve for people without frailty, the robust group, fifteen point five in patients who are pre frail, and the frail's 20. So, it's almost, an eighty percent increase with frailty in cancer risk in RA patients.

Now, did they factor in all the other things that would go along with frailty as far as disease activity that could also go with risk of cancer and bad outcomes. I don't think that was conclusively examined, but, I do think it underscores the idea that we should be, as we have talked about here and I've given, I had lectures at RheumNow Live about, sarcopenia and frailty in our patients, and that it needs to be noted, documented, and dealt with because it's kind of a bad prognostic sign, is it not? So, I think last week, we last month we published a nice review about IgA vasculitis, that was interesting. This week we had a report about the subset of IgA vasculitis that is necrotizing arteritis, and that's actually rare. In a literature search, they found thirty cases of IgA vasculitis that of the necrotizing arteritis type, compared that to two fifty seven simple IgA vasculitis and one hundred and ninety six PAN patients and guess what?

Having, necrotizing arteritis with IJ vasculitis is a very bad prognostic feature. They get life threatening complications. These people need to be, have vascular imaging. They need to have aggressive immunosuppressive therapy because the outcomes are ugly when necrotizing arteritis is seen. And again, that can be found both on biopsy, or suspected maybe even by imaging, right?

There is no biomarker that we know for this. An interesting study on gout from the Korean National Health, Service looking at claim data on four thousand one hundred patients showed that gout patients have a significantly higher risk of fractures compared to non gout patients. Five fold higher risks. What? But that risk went down significantly, with allopurinol use, and it was higher in those that were non compliant with allopurinol.

This risk of fracture, was seen with vertebral fractures, hazard ratio of five point seven and hip fractures four point two. The question is, why does gout and elevated uric acid or low use of allopurinol associated with a risk? It's not because of uric acid. Uric acid's antioxidant effect, it's not really panning out in any consideration of that. It looks like it's purely related to the induction of inflammation by uric acid in total body urate, and that control of that, leads to an inverse effect.

So, again, being compliant with allopurinol lowers the fracture risk, substantially in patients with gout. Something you generally don't consider when thinking about managing gout. Another thing I don't consider in managing idiopathic inflammatory myopathy is testing for RO52 antibodies. A lot in the literature about RO52 and where it stands. I think we talked about that during the interstitial lung disease campaign month, as being a potential modifier.

This is in China and Japan, a cohort of two thousand one hundred IIM patients and row 52 positivity was seen at forty six percent. It seemed to be even higher in patients who had dermatomyositis that was classified as either being MDA-five positive or being antisynthetase syndrome myositis, where again, it was a bad prognostic sign. Having ROW-fifty two associates with A, interstitial lung disease, B, rapidly progressive interstitial lung disease, and C, a poor outcome. So, is it like MDA-five, as a marker for rapidly progressive lung disease? Does it contribute to that MDA-five marker?

I think it does based on this data. Another recent report this week on the SELECT-two PSA, we've been talking about it a while. This is a sub analysis of the Select PSA two. This is a study, that was published this year, although it's been talked about for two years. It looked at the subset of people in the study who had to get in because they had failed therapy.

These were in biologics. This is the one hundred and ninety five, had active disease who had failed a prior TNF inhibitor, and then went either on upadacitinib fifteen milligrams a day or placebo, and at week twenty four, it proves a point that, when you're not responding to one drug, a TNF inhibitor, you should be switching MOAs because when you did, you got a sixtyfortytwenty ACR20fiftyseventy response respectively. So at week twenty four, the ACR 20 response was 58 versus 22, drug versus placebo. That's a 38% delta. That's very healthy, very strong, looks good.

ACR fifty, thirty eight versus 9.5, another 20 difference at ACR 50. MDA five was also different, 24 versus 3% and these findings in select two PSA that went onto the JAK inhibitor were maintained through week fifty two. Switching MOAs when you're failing an MOA makes sense. Again, the rule really is if you're a primary non responder to any MOA, you automatically have to change to another MOA. If you're a secondary non responder, meaning they responded and then after six months or more, they're starting to lose response, you could try another drug in that same class, but still you're going to do just as well.

Again, this is after they fail the TNF inhibitor, when usually the next biologic drug you choose, you're not going to get a sixtyfortytwenty, you're going get a 10 drop. In this study, they got a sixtyfortytwenty, that's why I think this is strong data. I have talked in the past about what to do in patients who have resolved hepatitis B virus infections. These are who? Patients who have no signs or symptoms, have normal LFTs, but and they are hepatitis B surface antigen negative, hepatitis B surface antigen positive would be active infection, would it not?

So these are a result in patients who are hepatitis B surface antigen negative, but they are core antibody positive, meaning that they saw the infection along a time ago, and they have antibodies against core and, core antigen. So this study looked at, is there a possibility of losing core antibody positivity and is that a good thing? They call that seroclearance of hepatitis B core antibody. So, this study of two thirty patients who were treated with, some of them were treated with an anti CD20 monoclonal antibody rituximab, They looked at it and they showed that seroclearance converting to core antibody negative status was only seen in sixteen point five percent. Who was more likely to have seroclearance?

Younger, CD mycophenolate treatment. Oh, it was less with those who were treated with rituximab and less than those who received mycophenolate. So overall, there were cases of hepatitis B reactivation, and in this study, was two point two percent. Let me come back to that. But of the five out of the two thirty that did reactivate, half of them had evidence of seroclearance.

The point is that seroclearance converting to negative doesn't mean that you're protected. I've talked about this in the past. Can you use a TNF inhibitor? Can you use a biologic in someone who has this resolved profile? Surface antigen negative, core antibody positive?

Yes, you can. What's the risk of reactivation of hepatitis B? It's low. It's one, two percent, which means it's not zero. You gotta watch them and you watch them closely.

If you're not sure how to manage these people, manage them in conjunction with a hepatologist. But they do not need to be on automatic antiviral prophylaxis unless they have other risk factors for, reactivation. I'm comfortable giving biologics to patients with this profile, knowing it's only going to be a one, two, you know, in a few studies, maybe three percent risk. U Star, which is a nice database that looks at systemic sclerosis and outcomes, they looked at the risk of cancer with four fifty four SSC patients and they looked at the development of cancer, either contemporaneously, they call that synchronous with the diagnosis or fifty, and that was in twenty nine percent, or fifty one percent who developed it subsequently. They had matched controls.

These were over age 55 or at 55, mostly female. Twenty eight percent had diffuse disease, thirty one percent had ILD, thirty two percent had anti topoisomerase antibodies, and ten percent had, anti POR3 or RNA polymerase RNA polymerase III antibodies. You know, the PolR3 RNA polymerase antibodies are seen associated with diffuse disease, more aggressive disease, and you usually diffuse patients. So, synchronous cancers were significantly associated with PolR3 antibodies, twofold higher, with U1 RNP antibodies, 3.5 fold higher, and smoking an odds ratio of one point five seven, but negatively associated with digital ulcers. Those who had digital ulcers in this registry seem to have less cancer, in fact, forty five percent less occurrence of cancers.

Developing cancer after the diagnosis also was associated with a few things. It was again inversely associated with calcinosis, so this skin, the calcinosis and digital ulcers, while those are ugly and hard to manage, the good news is they might get less cancer. Here was a fifty eight percent reduction in cancer risk. Breast cancer and lung cancers were the more common cancers that were observed. Breast cancer was also associated with POL R3 but also anti PMSCL antibodies, and lung cancer was associated with ILD, smoking and anti topoisomerase antibodies.

The aggressive markers of scleroderma give you the aggressive risk of cancer is the bottom line, but this study likes to look at it from the serologic standpoint, and you can use these, you know, RNA polymerase III, you can order. You can get topoisomerase antibodies, and that gives you prognostic information about this disease and this study would then also infer the potential for cancer risk. Why is this important? Cancer is the leading cause, one of the leading causes of death in scleroderma patients. Why not?

My last report is a launch to our obesity campaign. I think you're going to like a lot of the content, and the videos and the panels. Next week, we're doing a great panel discussion on Tuesday. I think it's the September 9, 7PM Eastern Time. It's TNR.

We're gonna do a journal club with, leaders in the field, the people who wrote the articles. We're going to talk about the STEP nine study showing that, GLP-one drugs work in osteoarthritis, and we're going to have, Philip Meese online to talk about the Together PSA study. This last report is about BMI affecting JAK inhibitor responses in RA. In this analysis, the authors looked at JAK trials with all five different JAK inhibitors, four different JAK inhibitors, think. It looks like, yeah, it doesn't really matter, that were registered in clinicaltrials.gov.

They found six trials, almost 12,000 patients, 7,700 of them had received a JAK inhibitor, Tofa, UPA, or Bari. The mean BMI was overweight, twenty six point eight, thirty one percent were, obese, class one, two, or three. Overall, taking a BM or overall, increases in BMI reduced the efficacy of JAK inhibitors in all ways that you looked at it, and it wasn't good. Compared to those who were of normal weight, overweight patients, when they got, a JAK inhibitor, their ACR20 response dropped six percent. That was significant.

Class one obesity, 30 to 35 kilograms per or BMI of 30 to 35, it dropped eight percent. 35 to 40 BMI, it drops twelve percent, and the most obese, over 40, it drops twenty to twenty two percent. That's a twenty two percent drop in ACR20 responses when you're morbidly obese and taking a JAK inhibitor in the clinical trials. That's significant. They showed parallel, data about increases in overweight, the dash 28 increased significantly by 0.14.

Class one, zero point two one, class two, zero point three zero, class three, zero point five four, Meaning that, you know, your DAS only got to, instead of getting to three with effective therapy, it only got to 3.5 if you're morbidly obese. Treating obesity is disease modifying therapy. Think about it. Tune in next week. Take care of yourselves.