Repurposing & Pipeline (8.8.2025) Save

It's the 08/08/2025. This is the Room Now podcast. Hi, I'm Doctor Jack Cush, executive editor of roomnow.com. This week on the podcast, we'll be talking salaries, vaccines, drug repurposing, and how are you sleeping? I hope you're sleeping good.

You know, that probably is one of the best vital signs I think we all have, we need to have. I found this study really interesting. It's about sleep and what happens if you sleep badly three nights in a row? It's a meta analysis of 35 studies, almost 900 people, and it shows that three consecutive nights of sleep deprivation, sleep deprivation defined as getting less than four point three hours sleep per night, was associated with significant increase in IL six and c reactive protein. I know I I always say sleep bad, feel bad.

Bad sleep takes whatever you got wrong with you, just amplifies it, makes it all worse. I guess the question is, is it just the sleep, sleep's effects on the brain, or has it got more pathology than that? Is there an element of neuroinflammation here? Anyway, a lot of studies proving the same point. A few reports this week on scleroderma.

One says that, and I saw this in Helio, and thank you Helio for putting this up there because I went and looked at the report, greater than thirty percent of patients with systemic sclerosis present with no Raynaud's. This was based on two large cohort studies. One showed like thirty percent, the other one showed over forty percent of patients who who were diagnosed with scleroderma, usually presenting with puffy fingers, musculoskeletal complaints, and then skin findings, but did not have Raynaud's at presentation. And what's different about those people? They tended to have more severe skin disease and they tended to have more musculoskeletal complaints.

You know, don't like making the diagnosis without Raynaud's. I immediately go into my tight skin other scleroderma differential diagnosis, but this says it's certainly possible and it's a sizable minority of people. The other report actually was just a review that said the good news is there's a big pipeline of drugs being developed for scleroderma. Most of us are not aware of this, but there are at least nine companies that are developing fusion proteins, peptides, small molecules, monoclonal antibodies, polymers, gene therapy, and I'm not even including CAR T cell therapies that are looking to include scleroderma patients in their trials. This comes from a lot of well known and not so known companies, Bayer, Novartis, GSK, Boehringer, Ingelheim, Celgene, J and J, Prometric, Cytori, Argentis.

I got it. I like it. I wanna see more research in scleroderma. Certainly, we need the help. Do we not?

Let's go on to another rarity, and that would be cryoglobulinemic vasculitis. This retrospective study of sixty three patients who either had essential mixed cryoglobulinemia with vasculitis or connective tissue disease related cryoglobulinemia vasculitis, showed that number one, these people flare. You know flares are part of the picture. So while you, in this study, they all went into remission with rituximab, and then they followed them out, for a median of fifty eight months, and relapse rates at one year twenty three percent, two years forty two percent, five years seventy one percent. Relapses were higher if they had purpura and had prior flares.

These are difficult patients to manage. Rituximab obviously is a good induction therapy, but maintenance seems to be problematic. Most of these people were on maintenance therapy. A study this week compared vaccine responses on JAK inhibitors and those that were taking TNF inhibitors. So they're specifically looking at COVID vaccine, the SARS CoV-two vaccine, and this was not a humoral study where they're looking at, you know, a fourfold higher change in antibodies against the spike protein.

This is a study looking at PBMCs and staining for gamma interferon production by CD4 T cells as a measure of vaccine responsiveness. And I think they had twenty two patients on JAK inhibitor 16 on TNF inhibitors. JAK inhibitor met criteria for a response, only fifty percent. Higher with TNF inhibitors, eighty one percent. So, you know, I have my rules, I tend to vaccinate everyone with two major, you know, rules, and one is methotrexate, hold the methotrexate for a week, and the other one is rituximab or B cell inhibition, vaccinate before or wait until six months after.

You know, the JAK inhibitors throughout COVID patients that were on JAK inhibitors, I vaccinated them, I didn't stop. I think I probably would want to stop here. Again, if you did vaccine outcomes in multiple ways, you might get multiple results, but there have been hints that on a JAK inhibitor you may not have the most optimal vaccine responses. This week, week we published a report on rheumatology salaries not being as high as you'd like them to be, that they're kind of flat. Added, that was data that was published on Medscape.

I added into that data that was published by Becker's and published on Doximity. And then this week there's another report on your salaries. This one coming from AMN Healthcare. AMN Healthcare did a long report on the demand, searches for certain kinds of specialties and what the salary is. Turns out that number one, internal medicine specialists or specialist MDs are in high demand in The United States, and that rheumatology is the seventh most in demand group.

Yet when you look at the searches, we're like last in searches. Turns out that the $20.24 salary low is a range here. It's a high, a low, and a median. The low 214,000. The high is 450,000.

Congratulations, whoever you are. The median salary is 341. Who are these people? I don't seem to hang out with them or be employed by them. They also had a lot of information in there about signing bonuses, benefits, and whatnot.

If you're changing jobs, wanna know what you're worth, I'd look at these reports, all three of them, Becker's, Medscape, and AMN Healthcare, and the link is in the notes. They also had a lot of information about advanced practice providers, NPs and PAs, where the average salary this last year, 2024, is 180,000, that's up almost 10% from 164,000 the year before. So while there's a big need for advanced practice providers, they're getting expensive, and I say they're worth it. This week there was a report on the use of patient reported outcome measures, PROMs, a survey of almost 40 Spanish rheumatologists, 50 years of age, ten years in practice, and while 80% of them agreed that there's an importance to doing, PROMs in practice, only twenty eight percent were doing them routinely. And at that they were mainly doing pain numbers, pain VASs, or a HAC.

The question is why are we not doing them? And the number one reason that they've said and that you said is time. I do a lot of PROMs. I do factor them in. It's on my survey form.

Patient fills it out while they're waiting to be seen. You should be using these. I like data about advances, especially in rheumatoid arthritis, potentially novel RA vaccine, and we've had RA vaccine studies. I did a vaccine study, gosh, fifteen years ago that failed. Or Angie Thomas in Australia has been working on an RA vaccine with a lot of success.

This one is an animal model where they developed a recombinant vaccine of HLA Doctor Beta one or four zero one bound to type two collagen, a type two collagen peptide that they modified chemically with a change in the glycine at position two sixty five, and they showed that when they gave this vaccine to a collagen induced, animal model, that expressed Doctor Beta one zero four zero one that they were able to suppress the development of arthritis. I like these results except they're in mice, and I happen to treat humans. So people are working on vaccines. It's out there, it could be part of our future. In Japan, there's a famous large scale IORRA study.

This is an early entry of RA patients from 2007 to 2021. Ten thousand patients have been enrolled. They looked at death, nine fifteen deaths amongst the ten thousand that they followed for this fourteen year period. That's about ten percent. Deaths were from cancer, lung disease, cardiovascular disease, making up almost sixty percent of the deaths.

Overall, these patients were protected as far as mortality outcomes if they were on methotrexate, if they were on a biologic or targeted synthetic No, I'm sorry, just a biologic DMARD, and it showed that low dose glucocorticoids, again, makes mortality risk higher. So that's not good news. Another one on death here. Let me see if I can find this one. I don't know if I can find it.

But anyway, next on my list is a meta analysis. These are kinda oldies but goodies. These are points that have been made before that you probably know about, but I'm gonna put them up there and remind you. The question is, do TNF inhibitors cause heart failure? Are you worried about heart failure with TNF inhibitors?

It's a warning amongst the warnings that are out there, and that's based on largely Amgen and Synacor data, but there is a lot of data from Fred Wolf and other large cohort studies basically showing that RA patients with heart failure, that's well controlled, get TNF inhibitors all the time with no untoward effects. This large meta analysis, 40 studies, a 150,000 patients, TNF inhibitors being used in a multiple, number of immune mediated inflammatory diseases like RA, PSA, SPA, IBD, showed no increase in A, de novo new onset heart failure, didn't happen, and B, people who had heart failure had no worsening when exposed to TNF inhibitors. Yeah, another oldie. I remember reviewing that data when I was on the FDA advisory panel back in the early 2000s. The same meeting, we actually reviewed the risk of significant LFT elevations in RA patients taking TNF inhibitors.

It was a rare event, really rare. It was like among 6,000 people on infliximab, etanercept, and adalimumab. There was, I think, 160 reports. The bad news was that almost all of them were with infliximab, a few with adalimumab. But most of them with infliximab, most taking five to ten milligrams a day, a lot of them complicated by background liver disease.

So the question is, does this happen? So again, a small retrospective review of nine patients taking etanercept five, four on adalimumab. These were, mostly female, BMI of thirty seven, over three years follow-up, their LFTs declined, their fibrosis scores, the FIV4 score, significantly decreased and their albumin and bilirubin levels stayed stable. This is just a reminder that, while you look at LFTs, I would say in RA patient on a TNF inhibitor with LFTs, I'd be looking at nine other reasons why LFTs are going the wrong way before I started considering the TNF inhibitor or stopping the TNF inhibitor. Another report that's kind of a duh oldie, but there's a lesson here, is lupus and its association with osteoporosis.

This is a study of one hundred and ten osteoporosis patients. Thirty five percent I'm sorry, one hundred and ten lupus patients, and in that cohort forty percent had osteoporosis. In that cohort thirty five percent had lupus nephritis. So it turns out that lupus patients with low BMD and osteoporosis or osteopenia, that was associated with lupus nephritis class III and IV disease, RNP antibodies, high CRP, longer disease duration, being older, abnormal HACs, and low complement levels. Eighty three percent were on steroids, that's duh, they got lupus nephritis, and they got osteoporosis, and they got lupus, and yeah, it's all probably from steroids, is it not?

But then again, let's think about it a different way. How many of your lupus patients, the mean age in this cohort was 48, how many of your lupus patients, even those in their 40s, are you thinking osteoporosis and the many things you do in managing your lupus patients? I don't, and I should. So it's not like I'm rushing out to do DEXA scans in my patients who are 31 and 28 with lupus and lupus nephritis. But if they've been on chronic steroids, maybe you should.

This is a complication, and it's a bad one, with significant downstream effects. A report from Arthritis Research and Therapy looked at how often GCA patients have a normal CRP. Again, a head scratcher to me, a retrospective study from France of three eighty patients with GCA found that twenty nine of them or eight percent had a normal baseline CRP of less than 10 milligrams per liter, less than 0.1 milligrams per deciliter at presentation, at baseline. GCA patients with a lower CRP level had less fever, more ocular complaints, especially anti ischemic optic neuropathy. That was seen in twenty eight percent versus thirteen percent.

More limb claudication, twenty four percent versus eight percent. But it turns out high CRP or normal CRP patients had a same number of, GCA relapses when followed out over time. So it does happen. It's got a slightly different presenting phenotype. Maybe the outcomes are the same.

Again, these were all proven to have the diagnosis either by biopsy, CT scan, PET scan, okay? Most of those being biopsy. GM CSF, there's been therapies that have been developed for GM CSF as a treatment anti GM CSF, it's a pro inflammatory cytokine. Those therapies are kind of problematic and whatnot. This was a drug repurposing trial, and it looked at what drugs might have effects that would correct the GM CSF excess.

Turns out that CCL17, the hemokine CCL17 is a downstream mediator of GM CSF, and in a drug repurposing exercise, they found five therapies that would have anti CCL 17 and therefore anti GM CSF effects, and these included, get your pen, paper, write these down, two of them you know of, fluoxetine, that's Prozac, ractopamine, r a c t o p a m I n e, don't know it, ponissimod, don't know it, terbutaline, heard of that, and etraverine. They all are associated with inhibition of STAT5, IRF4, and CCL17, and in animal models, these drugs have been shown to have anti inflammatory effects. I think drug repurposing is going to be a bigger thing in the future. The idea is there's been billions of drugs developed, a lot of them failed, a lot of them, didn't work as well as you hoped that they would work. The question is, as we get smarter about genetics and AI and different ways of looking at, how to use our older drugs better, smarter, Drug repurposing is going to be an important drug discovery exercise.

It mitigates the risk, the time, the cost associated with drug development. This is looking at molecular structures, looking at signatures, omics, lots of network based analyses with machine learning. I think you'll be seeing more of this. I published a few months ago a drug repurposing exercise of drugs that were shown to probably have potential benefit in osteoarthritis, a disease for which we don't have effective therapies. I would look for these going forward, and I would expect machine learning to play an important role of that.

My last report today is on the inefficiencies of ANA testing. This is an article from the Journal of Rheumatology this month. They looked at a single center cohort, a tertiary care center, and they researched the records of almost 2,500 individuals. And they found that in the ANA negative group and only two seventy one or less than ten percent of the two thousand five hundred were ANA positive. In the ANA positive group, only thirteen percent of the ANAs ordered led to a new diagnosis.

Most of those were RA or spondyloarthritis, but it's a minority, a small minority. Like, if you're considering spondyloarthritis or RA, why do you do the ANA? Obviously, it's not you, it's other people. Again, these were ordered for, you know, many hundreds of reasons from many different sources, most being primary care and medicine subspecialties that are ordering these ANAs probably inappropriately. In those that were ANA negative group, only one point six percent led to a new diagnosis, that being oh, wait, I got that wrong.

In the ANA negative group, one point six percent led to a new diagnosis, most often RA and spondyloarthritis. In the ANA positive group, fourteen percent led to a new diagnosis, them being Sjogren's, lupus, and UCTD. Overall, ninety seven percent of these thousands of ANAs that were ordered did not lead to a rheumatic or autoimmune diagnosis. So again, this is stuff you know. That's the kind of information you need to teach others about the appropriate use of the ANA going forward.

I want to encourage you again to look at your inbox tomorrow, Saturday over the weekend for the RheumNow. It's a cool little exercise. It takes a few minutes of your time. You get to see what you might have missed on RheumNow this past week, what you should have learned. You know, you don't always get them right.

I'm surprised. I think these questions are pretty easy, but the performance characteristic shows a perfect bell shaped curve with the average number of right answers around three and a half. That's usually at a six or seven. One that a lot of you missed last week was a true false. A South Korean study found that RA patients have a higher risk of gout.

True or false? The answer is true. And you heard me talk about this last week on the podcast. I say you can't have both, but we know it does happen in this particular study of thirty five thousand new RA patients, compared to a 103,000 controls show that RA has a 2.7 higher risk of developing gout when followed over time. That's on Room IQ.

You can take it next week and see how you compare to your peers. Take care of yourself. We'll talk next week. Bye.