Rheumatology Believe It or Not (4.25.2025) Save

It's April twenty five twenty twenty fifth. This is the Room Now podcast. Hi, I'm Jack Cush, executive editor of roomnow.com. This episode is gonna be called Rheumatology's Believe It or Not. Ripley is on vacation and I'm here.

Why am I choosing that? Well, we got like, the TriNetX database giving us data that's going to be interesting. We've got network meta analyses and other meta analyses and systematic reviews sort of cracking some of our beliefs. And we've got a review of guidelines that kind of let us believe our guidelines are kind of behind the times. Let's get into it.

A retrospective study on EGPA looks at what we should do when treating EGPA with meplizumab, and can you change the dose? Now, I like this because it brings up an interesting clinical option, although the data is based on forty five patients. So, this really kind of needs to be studied. Basically, these are EGPA patients treated with meplizumab and doing well at the initial starting dose of three hundred milligrams every four weeks. And then, some of them, a quarter of them, switched to a hundred milligrams every four weeks, and that was done after two years of doing well.

So what happens when you lower the dose, basically your maintenance dose, of meplizumab, or if you continue it. So, it turns out that fifty percent of these patients who lowered their dose were able to maintain complete remission without the need for other additional glucocorticoids. So, it's a small sample. The other half who got worse, they got worse in a minor way, with mainly upper respiratory sinonasal symptoms that were either treated with local therapies or going back to the initial dose of meplizumab. I think it's something that should be studied.

IL-seventeen inhibitors, as you know, increase the risk of IBD, and may be contraindicated in patients with IBD. The Trinetix database is a you see a lot of these, I report a lot of these. It's a linkage of, you know, many, many hundreds of thousands of electronic medical records nationwide, worldwide, and they find large populations, and then they do propensity matching to sort of normalize the data and make it more respectable. But supposedly, there's a lot of variance in how the propensity matching goes on. So, not all of this great high number, cohort data on things you usually can't study is going to be always perfect.

I think you have to know a TriNetX expert to know how this one was done, and I'm not a TriNetX expert. But I'm reporting that in their analysis of patients who have either psoriasis or ankylosing spondylitis, who were either treated with a started treatment with an IL-seventeen inhibitor or with a primalast, and they looked at what happened to them downstream. So in their hundreds of thousands, they found 13,000 that they matched up in each treatment group, and then they followed them. So that's like twenty six thousand people. One hundred and forty two developed IBD with IL-seventeen therapy, and sixty with aprimolast, giving the clear cut edge to aprimolast, or an increased risk of IBD with the use of the IL-seventeen inhibitors.

The adjusted hazard ratio here is 2.5, a 2.5 fold increased risk. Now, now there's a selection bias here, right? These people, even though they match them up with propensity matching, you know, those who choose to go on aprimilast versus IL-seventeen the inhibitor different. You don't use aprimavlast in ankylosing spondylitis, right? The risk of IBD with psoriasis and ankylosing spondylitis with the IL-seventeen inhibitors is mostly is significantly higher with, in the spondylitis patients, because, know, they have that subclinical ileitis thing, and just waiting to bust out and become overt IBD.

So, anyway, this data does support the current clinical contention. I'm not sure about the strength of evidence, but I put it out there for you to consider. Another IBD related issue is not IBD, but in this case gastrointestinal perforation, which you know is a risk of using IL-six inhibitors, but also JAK inhibitors. It's in the warnings for both compounds, or the multiple compounds, under those two classes of drugs. This particular study was a network meta analysis of 23 clinical trials with over 20,000 patients, followed at least for twenty four weeks, looking at the incidence of when you start a Jack or a conventional DMARD, the incidence of developing gastrointestinal perforations.

Those are usually lower, but they can be throughout the GI tract. The incidence here was zero point one nine percent, that's pretty low, and the numbers I think in the package insert for the IL-six inhibitors is like 2.6 and one point nine per one hundred patient years. So, even though that's a different way of accounting, that's kind of similar, but in this pairwise analysis, again a network meta analysis, they showed that if you were on a JAK inhibitor, you had no higher risk compared to those that were on a conventional DMART. So the relative risk was 1.02, not significantly increased. Know, I have a little bit of a concern about network meta analyses.

They always seem to show the point someone wants to make, and you are trying through statistics to compare apples and oranges. Meaning, these are not patients that are in the same trial. These are patients in different trials, in different countries, wearing different shoes, enrolled for different reasons, but they put them together because they meet entry criteria and they normalize the outcomes, whether it's a safety or efficacy outcome according to what goes on with placebo, and But in this case, they say there's no increased risk of gastrointestinal perforation. When I would say, based on the package insert warnings and claims data analyses done after these drugs were approved, IL-six and JAKs, there really still is a warning. But to their credit, I would say I treated a ton of patients with JAK inhibitors, and much more so than with IL-six.

And I've had one GI perforation with IL-six. I've not had any that I know of with JAK inhibition, and that's just my own personal experience. An N1 means very little. I like large number data. So, think about that and whether this colors your thinking.

Of course, you don't give the IL-six or the JAK inhibitor people who have a history of diverticulitis. Diverticulitis is at higher risk for gastrointestinal perforation, especially if they're on steroids. That's a contraindication to the use of those two drug classes. Who knows if that was in play in this network meta analysis? Probably was, because they use clinical trials, and people enter clinical trials under the most stringent of conditions.

Another interesting, meta analysis is coming up, I guess, on let me just do that right now. Meta analysis of methotrexate in knee OA. What? I did a trial of methotrexate in knee OA. Not inflammatory OA, OA.

I did that as I left Southwestern in mid-1990s. We enrolled twenty-thirty patients. The initial data cut looked encouraging, but in the end it was not significant. I never wrote it up. But there have been a number of trials, and we've reported them here, and most of you don't believe the data, and I'm kind of with you.

The good news is methotrexate's safe. The bad news is we have no disease modifying therapy for osteoarthritis of the knee. So, in this meta analysis they found six trials that met their entry criteria: a total of six zero two patients who enrolled to either receive methotrexate or placebo looking at NEO A. Not inflammatory in a NEO A NEO A. And they showed a significant improvement in pain with a mean difference of minus 0.44 that was highly significant.

P and three zeros and a three. And that was for relief of pain with either hand or knee OA. So they did have some hand patients in these trials. The functional improvement was only seen with knee OA, but there were no differences in the two treatment groups with regard to quality of life outcomes or adverse events. Are you using methotrexate to treat knee OA?

Why would you use methotrexate to treat knee OA? We just need really well designed larger trials to know that this is the thing to do. You know, today I was teaching a bunch of students, about scleroderma management, and I had an old slide that said there was no really no role for methotrexate, and I now know that that's not true. Methotrexate's highly effective in localized forms and maybe linear, scleroderma. In the form, not so much, okay?

At least looking at the major outcomes. But looking at skin outcomes with linear or morphia, very very good. Good data by Heidi Jacoby at UT Southwestern. Let's get back with, another interesting study, about the risk of developing lupus and what increases your risk. Guess what?

Worry is something to worry about. Systematic review of PTSD and its link to lupus onset shows in seven studies, five of them prospective cohorts, one retrospective, one case control study, Oh, eleven thousand six hundred SLE patients that, eleven percent of them had a history of PTSD as a comorbidity. This was mostly in females, but then again we're talking lupus here, I don't know what that means. All these studies showed, an association between PTSD and lupus as a in developing lupus, okay? And in three of them they showed a twofold increased risk of developing future lupus.

They looked at a number of other factors. I mean is there a genetic connection here between PTSD? And they did not find that. And there's a lot of data about stress inducing the disorders we take care of, including rheumatoid arthritis and lupus. PTSD may be the best characterized form of stress out there.

We still don't know what we don't know as to what causes lupus and these other disorders. My best guess and my best advice is avoid the PTSD, all those letters, avoid stress, and tell if you can tell me how to do that. Interesting thing about stress, I had a, I have I use a survey form in all my patients when I see them, and it asks them about things that they are experiencing, you know, are you working, are you exercising, do you have these, review a symptom symptoms. And I had one question on there for a long time with: What is your current stress level? Every patient, everywhere, under all circumstances wrote high.

Everybody believes you're under stress. And I don't know how true that really is. I believe that you either get stress or you give stress, so I aim to be the guy that gives stress. Sorry about that if I've done that to you. A nice review, on pregnancy and reproductive health guidelines and the use of DMARR therapy.

And I guess the purpose of this, you know, I say why did they do this? We just had the ACR guidelines on reproductive health, which were incredibly comprehensive. I know that I was on the committee. I think that Lisa Samaritano did an incredible job of looking over tons of information with a really expert cast of pregnancy autoimmune mavens, including representation by maternal fetal health and other specialties. And why do they do this?

Well, they actually reviewed, 18 current guideline recommendations for use of DMARDs, either with pregnancy or as it affects reproductive health. They found that the recommendations were quite heterogeneous, that they were all over the map, that only about half of them addressed preconception and conception, two thirds addressed lactation, one third only addressed male fertility. When it came to the use of conventional DMARDs and biologic DMARDs, three quarters or seventy two percent did, but only twenty eight percent addressed targeted synthetics, meaning JAK inhibitors. So overall, they found that the recommendations regarding the use of conventional DMARDs in pregnancy, either prior to or during, were pretty well covered, but not so much for biologics than targeted synthetics. And I know that that is covered in the ACR, Lisa Samaritano, ANR piece that you should be should have in your desk and refer to when this comes up.

They're concerned also about how we advise males and the use of our drugs, and how that may affect fertility and conception as well later on. We've discussed that in the past. Hip replacement is not linked to OA severity as far as the outcomes of hip replacement. So, OA severity might get you hip replacement, but what happens after you have a hip replacement surgery, as far as your mobility and your recovery, is not related to severity of the OA. It's actually related to muscle mass prior to the hip replacement surgery.

I thought that was brilliant because I think that was the key to my success with my bilateral knee replacements. I worked really hard on leg strength, lower extremity strength prior to my surgery and my recovery was great, Really great. So what they showed was and this is a small study, it's 10 patients who they did imaging, MRI imaging, looking at muscle mass and damage and whatnot, and they showed that it is muscle quality that best predicted recovery after surgery. So that should be your guidance to your patients. The best thing you can do for a patient undergoing hip or knee replacement is prehab.

Send them to rehab to strengthen their extremities before they have the surgery. Even if they're really obese or really out of shape, it's going to help them tremendously. And then I think that everybody that has joint replacement should have a rehab program, a serious rehab program, that sometimes the orthopedists don't want, but that you should push for. A retrospective study, by David Sherry in Philadelphia, who you know does a lot of work on pediatric fibromyalgia and pain disorders. He did a retrospective study of three thirty four children who had non organic amplified musculoskeletal pain syndrome, that's called AMPS, amplified musculoskeletal pain syndrome with back pain.

And they just showed that those who had localized back pain were more likely to have a positive straight leg test, meaning there's organic pathology in the disc and spine and nerve, right? And that was significant. But whereas diffuse amplified musculoskeletal pain in kids with back pain was more likely to have allodynia and a few other features, including what they called an incongruent affect. That's where they report pain, but they're still cheerful and happy and, you know, there's a disconnect between what you see and what you hear. Yes, this all sounds like fibromyalgia.

I think it was an interesting article. Another interesting article on obesity as a risk factor for not achieving remission. This is a cohort study of twelve eighty five early RA patients, a really strong prospective study, and they looked at those who did not achieve remission. Remission failure at six months was highest in those who were qualified as obese by BMI sixty four percent if you were obese fifty two percent if you were just overweight and forty eight percent if you were normal. So if you had normal weight, you had a fifty percent chance of not achieving remission.

Fifty percent chance of achieving remission if you're normal weight. But it's one third, two thirds achieving remission, not achieving remission if you have obesity. This did not change after they adjusted for seropositivity, education, smoking, alcohol, physical activity. Again, obesity a bad player. I want to see the data about newer obesity drugs, and how we're going to be using them, and what their effects are.

We know people do better in the RA, gout, lupus outcomes. We know they have less cardiovascular events, but can you be using these more purposefully to get obesity off the table so you can better manage your patients with, in this case, RA, early RA for that matter? I like to report this week about increased neutrophils in RA synovium correlates with higher disease activity and poorer response to conventional therapy and biologic therapy. So you don't generally think of the rheumatoid synovium the rheumatoid synovial fluid is just chock full of polys, right? It's kind of like the the sink or the toilet, if you will.

And that's where the polys will accumulate and then ultimately, contribute to damage to some extent, but not as much as that which is in the synovium. In the synovium, we know it's largely mononuclear cells that are driving the bus, that are causing the damage along with the fibroblasts. But in this study of fifty five patients, a third of them had enrichment for synovial polys neutrophils, and when they did analysis of those who had polys that were enriched and did not have polys, the ones who had polys had more synovial inflammation. They had higher -twenty eight CRPs. They had more CD3CD68 cell counts, also contributing to the inflammation and damage.

It's a different subset. So the things I'm worried about in RA not managing the fibroblasts and stromal cells that are causing all the damage our therapies do nothing for that. Our therapies generally do nothing for polys in synovium. These are other avenues that need to be explored going forward. A patient with RA is doing well on a TNF inhibitor and methotrexate.

What do you do? Well, a study from China looked at eighty four patients who were doing great on cerdulizumab and methotrexate, and they randomized them open label randomization to either continue on the double therapy or to stop methotrexate and just stay on cerdulizumab. And what do you think happened? Yeah, the patients who were doing well after you stopped methotrexate, they still did well. It was eighty five percent, achieved remission or stayed in remission or I'm sorry, remission low disease activity state on cerdulizumab and methotrexate versus eighty four percent on cerdulizumab alone.

But if you stopped methotrexate and went on cerdulizumab alone, you had less GI symptoms. So this is actually, something that we probably should be doing, and there are other studies that have suggested this. This is different though than patients who are doing well, and there's a Japanese study I can't remember it, I talked about it five, seven years ago, and it was backed up by another Japanese study: patients on methotrexate who are not doing well, and then you put them on a TNF inhibitor. What happens if you leave them on both drugs, or you stop the methotrexate and just put them on TNF inhibitor? It was done with etanercept.

If Artie Kavanaugh was here, he would remind me the name of the study. The study showed that you should continue the methotrexate, and that gives you significantly better responses. So adding on is different than taking away. Think about that. Two more reports, I think, that were impactful this week: better responses with baricitinib when you gave it at night.

What? This is called chronotherapy. You know, I don't know what you tell your patients. Some patients take the drugs at night, some take them in the morning. I tell my patients take them in the morning, get it over with.

I don't like it when they take it at night. But this data, a one year study, it's non randomized, it's open label, it's a few different regimens being compared. And one hundred and twenty two patients treated with either two milligrams a day or four milligrams a day of baricitinib, and they either took it in the morning or they took it in the evening. So there's four treatment groups here, right? Now, you've got to worry about it being non randomized and open label, right?

That kind of screws up any claims to fame here. But we're looking at ACR20 outcomes. The groups were fairly well balanced. In the end, baricitinib four milligrams given in the evening was significantly better than baricitinib four milligrams given in the morning: seventy eight percent versus forty three percent ACR 20s. What happens when you use baricitinib two milligrams in the morning versus at night?

Night was numerically better seventy six percent versus 61%, but that was not significant. But it was significant at certain time points at four, twenty four and fifty two, and VCR 50 at four and twelve. So it was kind of spotty. Numerically it was higher, and at times it was significant. So I think this is smart because one of the main things you know, hard discussion to have about what baricitinib and JAK inhibitors are doing biologically, but everyone agrees that one of the mechanisms is that it is lowering IL-six levels.

IL-six is clearly a cytokine that is produced in a circadian fashion and peaks at night, late at night. Okay? So giving baricitinib and other IL-six inhibitors at night is what you do. In my STILS patients who are going to take IL-six, I tell them take it at night for the IL-six effect. In my Stills patients who going take IL-one inhibitors, I say take it at night because IL-one is also a circadian cytokine that's peaking late at night, and anakinra only has a half life of six hours.

Take it at night. Chronotherapy is something we need to see more of, and you might want to experiment with this while we wait for a better trial to prove the point. Last, bit of evidence is you can prevent diabetes in almost anything by using hydroxychloroquine. This is a study of patients with primary Sjogren's Syndrome coming from, Taiwanese insurance claims data analysis, looking at 4800 primary Sjogren's patients on hydroxychloroquine versus two thousand four hundred not on hydroxychloroquine. By the way, why are these patients with Sjogren's Syndrome getting hydroxychloroquine?

I know you do it. It doesn't work. It's never proven to work. The guidelines and the review of guidelines on this have said that over and over again, but some of the guidelines, even despite the evidence, say Go ahead and use it for musculoskeletal complaints or pain. It does nothing to dry eyes, dry mouth.

Okay? Anyhoo, that's, my bias. But this study was about prevention of diabetes. April two thousand four hundred: five hundred patients developed diabetes after an average of five years. If you were on hydroxychloroquine, you prevented diabetes, and it did so in a dose dependent fashion.

So, less than three hundred, one hundred and fifty one to three fifty milligrams a day was a forty percent reduction that was significant. Has a ratio of zero point six. If you were on more than three fifty milligrams a day, it was a sixty seven percent reduction, with a hazard ratio of zero point three two six. As you might expect, patients on glucocorticoids had an increased risk of developing diabetes, and these are almost all type two diabetes, right? With an eighty three percent increased risk.

But if you were on high dose hydroxychloroquine and you got high dose steroids, you still had a lower risk of developing diabetes, and it went down thirty seven percent, and that was significant if the hydroxychloroquine dose was greater than three fifty. Again, there are so many reasons our patients should be on hydroxychloroquine, for all heart disease, lupus especially, but even in RA and Sjogren's, and wherever else it may have its benefits. I want to go back to this report about lupus and PTSD. I was going to save that report for next week, because next week RheumNow starts a campaign on lupus. It's called, unlocking lupus.

You, have the keys to mastering control of lupus. You're going to be shocked at the amount of volume we have of great reports, great contributors. I've been working on this with an advisory group of the world's best lupus experts, and what we've got coming up starting May 1 and throughout the month of May is really going to be great. It's going to be sponsored by Aurinia, thanks to them, and I think it's going to be a great learning month as far as lupus. And by the way, May is lupus month.

That's it for the podcast. Tune in next week. Follow us on RheumNow. Give us a good rating if you're inclined to do so. Thanks.