B Cell Depleters (2.21.2025) Save

It's 02/21/2025. This is the RheumNow podcast, and I'm doctor Jack Cush, executive editor with rheumnow.com. This week on the podcast, we're talking manpower. We're talking AI. We're talking ILD, cancer risk, all the good stuff, and we're gonna end it with lupus therapies.

So the national residency matching program published its 2025 results. I think we previewed that previously. We mentioned how well adult rheumatology match went, where of the 132 programs that we have, only three of them went unfilled. And I think that, you know, the numbers are up on the number of fellows that we're training. I think it's up to around two fifty a year right now, and that's encouraging.

I don't think it's gonna meet the gap we have with the growing need for musculoskeletal services. On the other hand, pediatric rheumatology, not so well. We have a major issue here. There were 36 programs that had open spots. Only 20 of the Sorry, 20 of the 36 went unfilled.

Only 16 of the 36 filled. We've got a major issue. We need a major effort. We need to incentivize people to go into pediatric rheumatology. I went into rheumatology largely because of my interest in pediatric rheumatology.

And for a while there, I was kinda confused about whether I was gonna be a pediatric rheumatologist or an adult. I just happened to be an adult who's done a lot of pediatric rheumatology, which by the way, the historical figures in rheumatology, John Baum, Jane Schaller, a whole bunch have exactly that path. They were internists who did pediatric rheumatology. Some other stats. The pediatric room program was number fifth, in the overall rankings with a number of osteopathic graduates.

That was interesting at thirty percent. And the adult rheumatology, match. Rheumatology had the fifth largest number of international medical school graduates. So that's maybe how we're gonna meet some of the manpower shortages by, going with DOs and foreign grads. And I think that's a great idea.

Lenny Calabrese, world renowned DO rheumatologist. Jack wishing he were as good as as Lenny Calabrese, a foreign grad from St. George's University. Lupus. I found an interesting, actually, I saw it first on on on the Cleveland Clinic news site where they referenced this TULIP extension trial.

You know, TULIP was a study of lupus patients, and the use of anifrolumab, or placebo and people on background standards of care. Usually, it's mycophenolate, hydroxychloroquine, prednisone. They showed you the two zero eight week results of three fifty four patients on anifrolimab versus five sixty one on standard care alone, showing that anifrolimab, those that were randomized anifrolimab, had about a sixty percent lower risk of organ damage as measured by the SLE damage index or the SDI. That was compared to those who were first enrolled to standard of care. So example here of aggressive treatment has significant downstream effects.

This is four year four years later that these people had less overall damage index by the SDI. I think that's encouraging. The question that often comes up, lupus patients who go into renal failure, Does their lupus get quiescent? Does it go away? Does it go away when they're on dialysis?

What happens when they get a transplant? Well, a meta analysis of 34 studies looked at this, 29 that were on either renal replacement therapy and five that were post renal transplant. They found overall that extra renal flares were seen in thirty six percent of patients with end stage renal disease as measured by the CKD stages. And it was higher actually in those that were on peritoneal dialysis or hemodialysis compared to those who had renal transplant. It was actually 4.3 fold higher.

And it makes sense. If you get a kidney transplant, you get back your renal function, and you're gonna do better. If you're on dialysis, you don't get back your renal function, you're replacing it. And then there are sort of pro inflammatory or extra renal manifestations that go along with hemodialysis. So it's obviously better to get a renal transplant if that's possible.

What's the recurrence rate of lupus nephritis in those who receive renal transplant? Three to four percent. That's a good low number. So the idea that they go into renal failure and their lupus stops is not really true. That's not been borne out by my experience over many years and by many studies that actually have looked at this, although that's often sort of the folklore that gets passed around.

A lot going on in lupus world. We're gonna talk about, obedentuzumab, as the last report today, but I wanted to review with you that there are three B cell depleting therapies that target anti CD 20 as their mechanism. Rituximab was approved in 1997 and has since been approved for use in RA, GPA, CLL, and non Hodgkin's lymphoma as also for pemphigus vulgaris. I did not know that. Ofatumumab, which has been studied in lupus and other autoimmune diseases was approved in 2020 for relapsing multiple sclerosis, and that remains its only indication at this point.

The, the newer one that to us rheumatologists is obedentuzumab. That was approved in 2013 for follicular lymphoma and then 2016, I think for CLL. It's a very popular drug amongst our hematologist oncologist colleagues. It has replaced the use of rituximab across the board. I think head to head studies and anti rituximab issue, antibody issues are much better with this therapy.

And right now, I just put up another report showing that ofatumumab and obinutuzumab are better than rituximab in the management of membranous glomerulofr phritis of multiple etiologies, mainly because there's less anti rituximab antibody secondary phenomenon that gets in the way of future efficacy, if not toxicity. So there are three out there. Only one is approved for use in rheumatology. That's only for RA and GPA. None are approved for use in lupus.

Yet many of you are using rituximab in lupus. I don't. I won't. I'll use it for ITP and refractory thry thrombocytopenia or autoimmune hemolytic anemia, but not for renal manifestations because it's been shown to not work. You can yell at me about the design of the trials and whatnot, but the good news is we're gonna see more in this area.

Give me a few minutes. I'll get to that at the last report. A Koreans claim database analysis looked at the risk of renal cancer in RA patients. Don't know why they were doing this. They compared risk of renal cancer, or I assume by this, mean hypernephroma versus a general population.

They showed that it was in fact increased thirty four percent and that was significant. And that this increased risk of renal cancer was unrelated to being seropositive or seronegative. It was somewhat higher in women with a hazard ratio adjusted hazard ratio of 1.57 compared to 1.34, but RA was not associated with other urological cancers, including bladder, prostate, or testicular. And I think that's been shown in other studies. Another study on cancer in RA was done in Australia where they compared fourteen thousand RA patients.

Average age was 65 years with thirty three thousand controls. And they showed that preexisting cancer in RA was less prevalent than the population, seven percent versus fourteen percent. But that new onset incident cancer in RA patients was actually lower in this study compared to the general population. And the CIR cancer incidence rates was nineteen point seven versus twenty four point eight. And that that cancer rate did not change over a three decade period.

Most other studies have shown RA cancer risk to be equal to the general population with SIRs of one basically or equivalent. But it's really misleading because some are elevated like lung leukemia, lymphoma, and skin, and some are decreased like breast, colon, and whatnot. In this study, they showed, that it was in fact lower compared to the general population, a little bit, not a tremendous amount, and it's been stable in Australia, but they did find that, the the cancer incidence rate was higher in RA for lung previously reported and hematologic cancers. By that, I assume they're meaning mostly lymphomas, but also some leukemias that have been that's panned out in other studies. Again, I wanna remind you the rules here are RA patients with a solid tumor.

Treat them as if they have no tumor at all. That means breast, colon, prostate, testicular, tongue. You know? Again, we can get into all kinds of arguments about melanoma and lymphoma. But if they have lung cancer, which is the most common cancer in RA patients, you treat them as you would treat them and and let someone else treat their cancer.

That's the way it's supposed to be. And that's in both guidelines from the ACR and EULAR. JAMA had a review this week on something we see related to cancer, that's MGUS, monoclonal gammopathy of undetermined significance. And the interesting points of this review, a good review, if you wanna look at it, is that the previous thought that, MGUS was associated with osteoporosis and autoimmune disease is not likely to be true. So that's, a reason not or to actually do SPEP and M protein testing.

MGUS by definition has no symptoms and has no organ damage. It's a benign condition that can be followed in the vast majority of people. Theoretically, you should only be doing M protein testing or S PEPs, if there's a malignancy suspected or if there is symptomatology and association with the monoclonal gammopathy. The risk of progression to malignancy from MGUS is low. I got a few reports on interstitial lung disease, still a hot button item here in rheumatology.

Korean national health insurance data, fifty thousand RA versus two and sixty one thousand controls followed for four years. ILD was seen in three point seven percent of RA patients versus zero point five percent of controls. That's an eight fold increase risk, hazard ratio of seven point eight four. It was higher in seropositive RA's hazard ratio of nine compared to seronegatives hazard ratio of four point eight. So ILD is a low frequency event.

Most studies in seropositive RAs have shown around eight to ten percent. This study looking at all comers shows it's only about three percent. Is that what I just said? Yeah, three point seven percent. So a Japanese study of seven eighty one RA patients showed that about ten percent of them developed ILD and almost all of those, or most of those were with the UIP pattern, which is expected compared to the other autoimmune diseases that we see scleroderma, lupus, myositis, where it's NSIP, right?

Mortality is higher when you have RA compared to general population, sixteen percent higher. But if you're RAILD, it's even higher than that. It's double that rate with a standard mortality ratio of two point zero nine. Again, the risk factors for mortality and RA were ILD, threefold increased risk, advanced age, eight percent increased risk, and a low BMI, another threefold increased risk. Obesity, we think is a big problem.

Being emaciated is a much bigger problem. So think about that. The prevalence of ILD and systemic sclerosis in a Chinese study of two thirty nine systemic sclerosis patients follow eight years was basically fifty percent, forty nine point eight. That amongst the SSILDs, two thirds of them had progressive disease with elevated CRP as the predictor. These people have a high mortality rate.

The mortality rate overall was twenty four percent with the main cause of death being pneumonia. Predictors were age, smoking, and high CRP for progressive disease with ILD, the rapid progressors, we talked about them before, and a high risk of death in those people. A survey of rheumatologists worldwide, mostly pediatric rheumatologists, one hundred and forty four, two thirds of them pediatric rheumatologists about their use of steroids in FAPA syndrome, also known as Marshall syndrome. This is one of those auto inflammatory syndromes with, lymphadenopathy and fevers and a bunch of other features. Most of them prefer steroids, ninety two percent, forty two percent expect a steroid response within twelve hours.

It's kind of spread out after that. Thirty one percent use steroids routinely in these people. And a literature search on this issue shows, prednisone is the most preferred steroid being used at forty eight percent. Again, response rates are really high. This is an auto inflammatory syndrome.

One that does not have a genetic association that's known. Two, does not, you don't run right into it with Anakinra or other biologics steroids are the preferred drug of choice. Although other biologics, including Anakinra can be used. My last three reports, think were interesting ones, targeting the programmed cell death protein receptor PD one has been used as a target for chemotherapy or immunotherapy in cancer. But, you know, we know that this is an activated marker on activated cells, and we now have monoclonal antibodies, rosenilimab.

It's being developed for use in moderate to severe RA. This is the results of the Renoir study, a six month trial where four twenty four moderate to severe RA patients either on or on background conventional DMARDs and sixty percent had previously received a biologic or targeted synthetic. They were randomized to either placebo or one of three doses of rosinilimab, either a hundred or four hundred given every four weeks or six hundred given every two weeks. The primary endpoint was a DAS CRP at week twelve, and then week fourteen was also important. They also looked at CDAs.

Bottom line at week 12 and in 14, pretty much all of these measures were significantly, higher for, pretty much all the doses. DAS CRP, was significantly dropped. The Cdies less than 10 was achieved in forty six percent, fifty percent, and 38% on the six hundred milligram versus 31% on the placebo. And then, the ACR 20 was 69%, 70%, and 75% versus a 53% placebo response. Note if you will, the placebo response is 53.

What does that tell you? That is a high placebo response. And yeah, you need a Delta treatment effect of more than 20% to be significant, and they achieve that here. Why do they have a 53% placebo response? This is probably a worldwide trial.

We've discussed that in reviewing ACR data and UR data that placebo response rates are highest in countries with that are the poorest. And right now there is less studies being done in North America and more studies being done worldwide, especially in poor countries. And you see high placebo response rates that gets in the way of interpretation. But in this study, it looks encouraging. By the way, this data, which is, I guess, in phase 2B, I think it's a phase 2B study.

Yes, it is. Is a follow-up of an earlier phase two. I think it was reported by Paul Emory. I think showed modest results. I think this is more encouraging, and I think this means that this drug is gonna go forward in drug development would be my guess, because that was not discussed.

JAMA, not JAMA, the American medical association published the results of a US physician survey in 2024. They just completed that. Well, they also did in 2023 and it looks at physician attitudes regarding artificial intelligence. And generally, it looks like you're starting to accept this. While there are many of you, 40% of you are like, I don't know, that AI stuff looks goofy to me.

Looks like someone's cheating, not reliable, whatever you wanna say, it's not good, more are encouraged. So that the number of physicians, not rheumatologists, physicians who say that there is some advantage to patient care is now 68 up from sixty three percent in 2023, that there's been substantial growth of AI in practices that has nearly doubled in 2024, sixty six percent in 2023, it was only thirty eight percent. There's been a dramatic drop in those who said, I'm an AI non user, count me out. It was 62% a year ago, it's now only 33%. And that's just in one year, it's very fast as far as healthcare technology adoption.

And then again, the greatest growth has been in the use of AI for documentation, discharge summaries, care plans, planning research and standard of care summaries. If you're not doing it, look into Claude, look into CHAT TPT-four, look into Gemini, find one you like and use it. We do, I do, and I think it's important. Lastly, obedentuzumab, the anti CD20 monoclonal antibody has been studied in a phase three trial in patients with active lupus nephritis. It is a humanized antibody previously approved for follicular lymphoma and CLL.

This is a phase two trial, two seventy seven biopsy proven lupus nephritis patients who either got placebo or one or two doses of obedentuzumab, and they were followed out for a year. Actually, the results they're reading here in this New England Journal article was at week 76. So one hundred and thirty five received obentuzumab, one hundred and thirty six placebo. Primary endpoint was a complete renal response along with a few other things, complete renal response being a UPCR of less than 0.5 with a GFR of at least 85, no other problems, no other flares, no death, whatever. Again, the primary endpoint was achieved in forty six percent with the CD20 monoclonal and thirty three percent with the placebo.

That's a P value of 0.02. More people on the anti CD20 were able to get their prednisone down and tapered per protocol forty three percent versus thirty one percent on placebo. And UPCR of less than 0.8 was also more common with obinutuzumab at fifty six percent versus forty two percent with placebo. Again, this is going forward. I would hope that we see this anti CD20 monoclonal ultimately do well in a phase three and hopefully get approved for use in lupus.

That's it for the podcast. Look for a number of the things we're gonna put up. We're gonna put up a few step talks. These are like Ted talks. One's on the website right now.

Artie Cavanaugh talking about, RA and liver disease. You wanna check that out and you're gonna look at mine, in the next week or so on RA flares. Is it a crisis or is it an opportunity? Check it out on the website. Take care of yourselves.

Bye bye.