Troubles with ‘Gut Feelings’ Save

This is the RheumNow podcast for 10/16/2026. I'm Jack Cush with RheumNow. This week on the podcast, placebo trumps controversial therapies. You know, disease activity is a moving target. For goodness sakes, fuse the big toe, and patients don't really like it when you say it's all in your head.

Let's begin with things that we think are probably a good idea or there's at least people saying so. I got a few items in this category starting with probiotics in psoriatic arthritis. A single center study of patients, sixty six patients with moderately active psoriatic arthritis. They're on stable therapy. They give them probiotic or placebo for twelve weeks.

Only fifty six are analyzed. Not sure why there's ten dropouts, and their response is a PASDAS of less than 3.2. The probiotics did not beat placebo, forty six percent versus sixty five percent in placebo. That darn placebo is such a good drug. That's not significant.

It's almost inferior. And other sub studies they did, like gut permeability markers and stool microbiome contents, did not change significantly because of it. And that's sort of the objective here. Give the probiotic, change the microbiome, and your health gets better. We've done reports on micro...

On probiotics in RA before, but never in PSA. It's a mixed bag. Sometimes it works, sometimes it doesn't. These aren't the best studies as far as construct and numbers, but it's a common thing that's out there, and I'm all for, homeopathic natural therapies, nutraceuticals when, a, they don't cost much, b, there's no, safety downside, and, c, the patient seems enthusiastic. And I've used a lot of probiotics in RA and PSA with some mixed results myself.

I think this study is really what the landscape is. Sometimes it works, sometimes it doesn't. It's up to you to figure out whether it's worth to support the patient or to be totally evidence based and dictatorial. That doesn't come off very well either. More on that later.

What about the value of family history in, when you're evaluating rheumatic patients? Know, this is an opinion piece here. I don't really have good evidence here. There's a literature review about that most of you are asking about family history and you're very diligent about it. I don't think it's worth very much at all.

Other than ankylosing spondylitis, gout, and DIP arthritis, everything else pretty much isn't really helpful. Yes, I know we all have patients. I had a bunch of patients, when I was at the county hospital, where they had prednisone next to the salt and pepper shaker on the kitchen table because everybody in the family had lupus or a variant of autoimmune disease. That happens, but it's rare. And then how do you know that the mother or grandmother really have the disease knowing that a lot of that is misdiagnosis?

The literature says that there actually is a high heritability factor for lupus RA, systemic sclerosis, Sjogren's, and autoimmune endocrinopathies, meaning thyroid related diseases. But yet I think... I I still ask about family history, but I'm not gonna spend twenty minutes on this, and I don't... I'm not gonna map it out genetically. I don't think it really is fruitful, but I asked people on Twitter what they thought didn't get many comments.

What do you think? A UK looked at, are women with autoimmune disease being treated fairly? That seems to be the bias of why they did their survey. They surveyed six thousand six hundred autoimmune disease patients, more than two thirds of them were from The UK, ninety one percent were female, and what they found in this survey, again it's got a little bit of a bias, that females had a longer delay to diagnosis, they were going to have more, medical visits and they were more often told significantly so that their disease was in their head, that it was a psychiatric problem or a psychosomatic problem. The numbers here odds ratio one point five six, forty three percent versus thirty three percent that it's psychiatric.

Really a third of my autoimmune patients are being... Someone mentions it psychiatric. What's going on there in this study? I don't know, but I do think this happens. So there's, it seems like there's about a fifty to eighty percent likelihood with females being told it's psychosomatic or in your head.

There was no significant difference in misdiagnosis between males and females. The number is not important. So what do you make of this? I think that, males and females are different and I think how you treat them needs to be different. I think telling people that it's in your head is always insulting, whether it's true or not.

And I think you're gonna have to navigate that one more cautiously. An annals of internal medicine report put up an interesting study of advanced practice providers, APPs, and showed that, in a survey of four studies, four states, excuse me, that, on average one third of the APPs were trained in for profit programs. 41% in California, 35% Florida, 21% Texas, 15% Iowa. That one third number in here in 2024 is up from 2.4% in 2010. This is the way of the world in education and training these days.

There are a lot of for profit institutions that are arising. The worst part in my opinion is that when private equity gets involved in this because private equity wants to buy something that they can sell and sell it at a profit at any cost. Quality of education often suffers in situations like that. I wouldn't say that this one third of APPs were trained at for profit programs are being shortchanged or inappropriately changed, trained. I think that it is, very much a function of who the ownership is because there are a number of for profit ownerships that are really committed to education and do it really well.

This is, important because it is expected that the growth of APPs in the next decade is going to be about 35% versus only 3% growth in physicians, meaning that there'll be more and more APPs hired. Should that color the way whether you, or not you consider these folks when you're interviewing them? I would say no, because, it is the interview, it is their intellect, it is their letters of recommendation, and in the end, you're gonna train them in rheumatology, are you not? It's important. Let's get into lupus a little bit.

University of Toronto, has a famous lupus clinic, that they've done research with over the last many years. This is a study of a 165 biopsy proven lupus nephritis patients with a disease duration of six plus years, and half of them are on antimalarial therapy. And the question they asked is, does chronic antimalarial therapy, hydroxychloroquine and the like, change the renal outcomes, the renal biopsy outcomes? And in their study, being on an antimalarial did not alter the renal biopsy outcomes, and that means how many progressed to proliferative GN, the activity index, chronicity index, etcetera. So hydroxychloroquine did not change renal biopsy outcomes, and we all preach that all lupus patients should be on hydroxychloroquine and then you add on top of that, do you not?

But you know the literature does show that hydroxychloroquine, does improve renal outcomes and morbidity mortality outcomes in patients with lupus nephritis. So, I think this is... Even though it doesn't change the biopsy results, there are other parameters of outcomes here that are equally important and hydroxychloroquine, not in this study, but in other studies, look it up, has been shown to pretty much benefit all outcomes in lupus. Another study in this one was in moderate to severe, discoid lupus presented this last month at the EADV, that's a famous dermatology meeting. Daxilimab, an anti ILT7, a plasmacytoid dendritic cell, marker, can be targeted with this daxilimab, daxilimab, a phase two randomized controlled trial of seventy two refractory DLE patients were treated either with placebo or DAX and they had two different outcomes.

A classy A response, was really significantly favored, the biologic over placebo at week twenty four. The percentage of people with a greater than 50% improvement in class e a at week four was sixty two percent versus twenty four percent. What's important about this? One, more therapies targeting plasmacytoid dendritic cells. Two, another biologic that seems to be poised for use in lupus.

Three, using cutaneous lupus as an important outcome in lupus that could be used for registration on a new drug. These are important trends that are going on in rheumatology. A study out of Singapore looked at, MDA five associations in patients with idiopathic inflammatory myositis, polymyositis, dermatomyositis. MDA five is more common in Asian populations than it is in The US. So this is a study from Southeast Asia.

They found MDA five in thirty five percent of the DM patients that was kind of high. Again, of all their one hundred and nineteen myositis patients, DM was more than half, the antisynthetase syndrome was about a quarter, necrotizing myositis was a minority at four percent. MDA-five had significant associations with dermatomyositis and that's we know to be true. Also had more skin manifestations that we know to be true. That includes digital ulcers, palmar papules, Gottron's lesions, heliotrope rashes, and periungal erythema.

MS, musculoskeletal symptoms and CK elevations were higher and more prevalent in the antisynthetase patients compared to the, MDA five patients. But as expected, ILD associated with dermatomyositis was more prevalent with the MDA-five. I now test for MDA-five in my patients and a lot of them have been positive and my, the outcomes are nasty. Those patients need to be closely followed, aggressively treated, not the point of this particular report, but certainly, mirrored by this report. What about methotrexate in scleroderma?

You know, do you use it? Turns out a lot of you do. I have at times. This was a study of ninety two patients with early systemic sclerosis. They were all treated with methotrexate.

So it's a cohort study, no matched or comparative, therapy against methotrexate. Seventy nine, eighty percent had diffuse, systemic sclerosis. At three months, thirty four percent of the diffuse patients had a greater than twenty five percent reduction in the modified Rodnan Skin score. That increased to sixty two percent by two years, but there's a reporting bias. They stayed on the methotrexate, well, for good reason.

Right? And, you know, I I think that it says that there might be a benefit there. But if you look at the literature as I did after I published this on RheumNow on Twitter, there's modest evidence of benefit and modest benefit in systemic sclerosis with methotrexate and mainly just skin. No other outcomes have seemed to benefited from the use of methotrexate. But there is evidence from two randomized controlled trials in this observational study that skin may benefit.

I wouldn't give it for bad organ disease, renal disease, lung disease, patients with a poor prognosis and whatnot. Obviously, they need other therapies with or without methotrexate, and that would be my take home from this report. A study out of The Netherlands looked at the prevalence of symptomatic hand OA showing that in the last decade that the incidence of hand OA has increased from... And that's from 2013 to 2023 and increased by sixty five percent. Now was that better recognition or a real change in the incidence here?

It went from five point seven cases, five point seven percent to nine percent, in their population based study. The The study of one point eight million Dutch patients 30. Prevalence rose sixty five percent, incidence rose twenty percent from seven point one to eight point five per one thousand. You know, obviously, we see a lot of hand OA. Again, there's no way of knowing from this kind of population should be whether it's a true increase or an ascertainment bias.

You know, I've talked in the past about the use of, cheap and easy inflammatory markers. You know, my favorite is the neutrophil to lymphocyte ratio, NLR. There's also the platelet to lymphocyte ratio. You know, those are CBC numbers. You can just do the math on and figure out if they're inflammatory or not.

I came across another one this week. This one's called the prognostic nutritional index, the PNI, was studied in nine hundred and eighty four patients and showed that the PNI was inversely correlated with RA disease activity, especially if the PNI is less than 45, meaning low. Low PNI, high disease activity. The PNI is a calculation of the serum albumin, and the lymphocyte, absolute lymphocyte count. And you can look at the citation to do the calculation.

It's not a five finger, 10 finger calculation. You need a little calculator and a formula to do it. But, you know, it has been studied in other inflammatory illness, illnesses and it's shown to have a modest correlation that AUC of like point six six. It might be better if it was point eight or higher. But, again, it's free.

It's cheap. It is easy. You could program that in... Into your EMR along with the NLR. And before you order a Sedrate CRP and full panel of whatever you like to order, we tend to order too many lab tests, you could have a good indication.

Another pet interest of mine is demyelinating disease with TNF inhibitors. And that stems from long ago, twenty plus years ago, I used to write ACR hotlines and one of the first ones I wrote, I think Rob Spire and I wrote it, was on demyelinating events with TNF inhibitors with an early, safety report coming from the FDA. This would have been around 2002 or so. And the report back then was that it looks like TNF inhibitors may induce demyelinating disease. By that I mean, multiple sclerosis and optic neuritis, de novo new events with the use of a TNF inhibitor.

And it looked like A, it was more frequent with etanercept than the antibody based, TNF inhibitors, and B, it seemed like it was more frequent in my report in seronegative RA patients. Anyway, that wasn't really addressed in this particular study of two hundred and fourteen thousand, RA patients, a half of them were on, not half of them, one fifth of them, about forty thousand were on TNF inhibitors, and overall from two hundred and eighteen thousand overall, they had five sixty two demyelinating events over about a 15 period with a cumulative incidence of zero point three two percent over ten years. You know, it's not very good. The incidence with, if you compare that with TNF inhibitors, the zero point three two percent cumulative incidence and compared it to those who were treated with just conventional DMARDs whereas zero point five percent, it shows a significant difference. Hazard ratio one point four seven and that is significant.

But still, these events are rare. I mean, since I did that report in 2002, how many demyelinating disease events have I seen in my thousands of RA patients over the years? Very few, maybe like two. How many was this issue an issue when the patient had preexisting optic neuritis or multiple sclerosis? Should I give a TNF inhibitor or not?

I always did. I never was burnt by that. The other thing was Sergio Schwartzman and I did a, FDA review looking at the maligning events for all biologics, IL-six, IL-one, T cell targeted, TNFs, B cell targeted. It happens in very low frequencies with all the biologics, and that's the take home. These are rare events.

I think when you get this rare event on a biologic, especially a TNF inhibitor, you may be obligated to change really more for medical legal reasons because we don't know the outcome of those people, but also usually you're going to have many other options. Have I kept some patients on those drugs? I have, but that's usually because they didn't have any other options. Next, can you, reduce DMARDs in RA patients? This is Korean study.

I didn't like this study because I'm always on a rant saying don't withdraw therapy, don't wean therapy, whatever. Well, you want to go with this one, go with this one. Close to ninety percent of patients with RA were well controlled on on targeted therapies and were able to reduce their therapies by fifty percent without worsening disease activity. Now reducing is one thing and maybe you can get away with that, but stopping is always going to be met with a flare in more than thirty, forty percent of patients, which I think is not worth it. But if you want to reduce, here's a study from South Korea, was on, it was a full report actually from MedPage today that I republished, that says that you can do it.

Another interesting report on disease activity comes from Core Evitas. This is, the old corona database run by Joel Kremner, and Joel Kremner is the lead author on this. And they make the point, Kremmer, Weinblatt, a few other authors, in their study of six thousand eight hundred RA patients that are, in low disease activity. They have a CDI score of less than 10 and when they looked at these patients and they compared those who have very low disease activity, remission would be less than 2.8. Very low disease activity is two point eight to six, that was nineteen, almost twenty percent of their patients, versus those that were in higher low disease activity, to ten, that's thirty one percent of their patients, that six to ten group had twice the likelihood of progressing to moderate disease activity in the next one or two years.

The point being that the lower you go, the better the patient's gonna be. The lower you go, the less likely they are going to dynamically sporadically change into another category high or very high disease activity, or moderate disease activity. This is something that I've noticed in the past. I did a study when I was a fellow with Chet Fink on Posse Immune JIA patients. I think I had like two sixty Posse Immune JIA and Posse Immune oligoarthritis and JIA is one, two, three or four joints and your Posse Immune in the first six months.

And I looked at what was going to be the outcome in the course beyond six months. If you had one joint and or two joints in the first six months, you know what, you are very likely to stay pauci immune. But you know what, a small number of the two joints did progress to polyarticular JIA, right? But if you had three or four joints in the first six months, almost all... Well, certainly the four, the majority, sixty percent progressed to polyarticular JIA.

Again, disease activity is a dynamic thing. At every visit, the patient should be in remission. I don't like lotus activity, I like remission, and I don't like using excuses why I can only get to lotus activity, so I'm always pushing on what my options are and people like that. So what do you do with early disease? Brand new disease, what's your first drug?

Yeah, everybody goes on methotrexate. I got a lecture I'm doing right now, I hope you can hear it sometime soon. It says use your best drug first. It's a line I stole from Fred Wolf. And the gist of my study is JAK inhibitors are better than methotrexate.

JAK inhibitors should be your best first drug, especially with its $25 a month as generic tofacitinib from Cost Plus Pharmacy in The United States. That's not a very popular, opinion by the way, it goes against ACR and UR guidelines. So here's a study, a meta analysis of 29 RCTs in early RA. Patients, they're getting their first drug. This is thirteen thousand three hundred eighty seven patients.

They either get a biologic or targeted synthetic therapy first or they get methotrexate first. And some of these people got the biologic with methotrexate, and they compare it to just methotrexate alone. Initial biologic targeted synthetic therapy plus or minus methotrexate was significantly better at achieving a dash 28 remission of of of less than two points... At six months of less than 2.6. And the...

Again, the the numbers there were... It was sixty two percent higher than methotrexate alone. If you use methotrexate alone in all early DMR naive patients, one thirty three to forty percent of patients are gonna respond. The number is higher if you use the more aggressive therapy. Should you do that?

Can you get away with that? I'm scratching your lizard brain and making you think about that. The benefits were greater with higher baseline activity and in patients who were seropositive. Interesting. Two more reports.

Someone asked me about a month ago and I've been mulling about a low dose naltrexone. And this was a rheumatologist, community practice who had started to use it in fibromyalgia patients, chronic pain patients said, you know what? It's cheap, it's easy, it seems to work in some people. So, I found a report this week. It was a...

Not quite a meta analysis, a narrative review of a 105 studies, 15 randomized controlled trials, and the answer of whether you should use low dose naltrexone in pain or in rheumatologic conditions is no. Let me just say it again, no. And this particular study said, although there are weekly positive study results from uncontrolled trials and single case reports, it's never replicated in a placebo controlled trial. That the evidence that's out there out there is highly biased, a high publication bias, these are small studies, single reports, and the outcomes are very subjective. How are you doing?

There are not many ACR 20 or dash 28 scores in in these kinds of studies. There might be a bias, that it might work centrally. Again, naltrexone is approved for alcohol withdrawal and opioid... Avoiding opiates in higher doses. This low dose naltrexone, its mechanism, how it works, four point five milligrams a day, it's cheap.

It seems to be really safe. Mechanisms are, I think, speculative. I've not used it and I'm probably not going to use it, but I put the evidence up there for you to play with and tell me your experience. Lastly, there was an annals of internal medicine report on ninety patients with hallux rigidus MTP1 OA that was active, pain on walking, limiting function, and this was a study done in Finland. It was funded by a research, foundation, so there's no reporting bias, or funding bias here.

They did not include RA patients, diabetics, or patients with a severe angled hallux, valgus deformity. So these are patients we would call hallux rigidus. They have pain, and the intervention was either watching them or doing a first MTP arthrodesis, thankfully done by the orthopedics. At twelve months, significant improvement in the arthrodesis group. Their VAS pain at the end of twelve months was 1.3 for the arthrodesis group versus 5.7, this is on a zero to 10 scale in the weight and watch group.

Why would you not do it? I think you should do it. It is, I must say, in all my patients, I've never done a good job, counseling them on what the aftermath of foot surgery is. The aftermath of foot surgery is rough. It hurts more than other parts of the body in my opinion, the recovery is harder, the need for physical therapy, is to my mind absolute, so you need to prepare people.

This is not easy surgery but if they want to feel much better and have less foot pain on walking, in a year, fusion of that big toe might be the right thing to do. Two reminders. One, registration for RheumNow live is open. We'll look to see you there. And two, you can ask a question, present a case to me, make it short on ask Cush anything, click on the box on the website and record your case, and we'll discuss it here.

And lastly, Room A bunch of you are doing Room IQ quite successfully. It's a great way to learn the week's news in addition to listening to the podcast. Log in, opt in. Last week, I'm always going to talk about most of you did very well. The average score on last week's eight question quiz was 70%.

That's pretty good. However, only 45% of you got this question right, which is in a psoriasis cohort, which biologic class was shown to best prevent progression to psoriatic arthritis? And the choices were TNF inhibitor, IL seventeen inhibitor, IL twenty three inhibitor, or IL twelve twenty three inhibitor. The right answer was the IL twenty three inhibitors followed by IL-seventeen, then twenty three, then TNF. But the point of the paper was that biologic therapy in psoriasis seems to prevent progression to psoriatic arthritis.

I think we've said that here 10 times, and these are all observational studies, so it's not proof, but it seems highly suggestive. That's it for this week on the podcast. We'll talk next week. Take care of yourself.