ERA, APPs, & Alpha GAL (3.21.2025) Save

It's the 03/21/2025, and this is the Room Now podcast. Hi. I'm doctor Jack Cush. I got a scratchy voice this week. I was yelling at the hockey game tonight.

We lost in overtime. So you're just gonna have to go with something that sounds like Jack Cush. This week, we're gonna go through the news, and we're gonna end up with a few, interesting cases, called Ask Cush Anything. So let's start with, lessons in machine learning and AI. You know, the question is, where is it going to fit in?

How is it gonna work? Is it really something we can use now? And I like this study coming out of Morocco. It's a single center study of 112 RA patients, and they use a number of different machine learning models on their cohort of patients to identify patients with depression. And they had a survey that they used called the HEDS survey, and they showed that they found one of the models that performed best and ultimately had like roughly 80% accuracy and precision.

Its AUC was again about 77%. And the idea here is that AI can be working before you do your work. I can imagine the day when I ask AI when I sit down to open my tuna fish sandwich at lunch, please scan my patients for the month of, you know, of March and tell me who's at risk for depression. Who do I need to be paying attention to? Use AI to identify of the patients that you're following, you know, who needs a follow-up visit that hasn't been seen.

Again, AI can be doing tasks like this that will make you better, that when you open up the chart, AI will prepare for you, the things that you need to be paying attention to at this visit, or on these in these cohorts or in these individuals. I think this is really where we're going. There was a ARD paper this week from Ron van Vohlenhofen's group from The Netherlands, where they looked at at risk patients with arthralgia and seropositivity. There are six seventeen patients. And like all other estimates, if you look at seropositive, preclinical RA, clinically suspect arthralgia, at risk patients with just arthralgia, no synovitis, about a third of them, thirty percent, are going to develop inflammatory arthritis.

And that's exactly the number they saw here. It was thirty three point seven percent. And the average time from time that they followed the patients to developing arthritis, and those that did develop arthritis, was about twenty months. The risk factors were, as we have said before, and I put it up here because I think it's we struggle with what to do with these people. The ones who are at highest risk, fivefold higher risk, high titer ACPA antibodies.

Or even higher, almost sevenfold higher risk, for being double positive for RF and for ACPA. Other factors: first degree relative intermittent symptoms: less than twelve months of symptoms AM stiffness greater than an hour reported joint swelling by the patient, even though you may not have discerned it. If you had three or more of these variables, the number went from not thirty three percent, but fifty eight percent of patients who subsequently developed inflammatory arthritis. I think that there's an important lesson there about how to consider these patients going forward. I found another interesting article this week it's a preprint actually from Mike Brenner's group, where they did spatial transcriptomic profiling of RA synovial tissue biopsies.

And they had paired biopsies pre treatment and post treatment. And these would have been patients who were, I guess prior to treatment they got the biopsy, and they were either treated with conventional DMARDs or adalimumab. And when they looked at the post treatment synovial biopsies, and what was the transcriptome telling them, that one, there was a lot of these fibroblasts and stromal cells that are unaddressed and are probably the cells that are doing all the damage, even though we may be controlling the disease. And then more importantly, they found high expressions of COMP and TGF beta. All of this is driving basically synovial tissue fibrosis.

They make the case that these potentially are going to be therapeutic targets, meaning maybe targeting TGF beta might be another way of turning off this fibroblast activity that's not yet being addressed with all our very good therapies in RA. A report from ARD also looked at the use of colchicine in familial Mediterranean fever patients who are pregnant. To answer the question: Is colchicine safe during pregnancy? And there are other studies that have looked at this. So this particular study was actually a meta analysis, a systematic review of 25 such reports.

Miscarriage was not increased on colchicine. The relative risk was zero point eight seven and overlapped one. Secondly, birth defects were similar between those exposed to colchicine and those unexposed, and are within this hard to know number of what is the birth defect rate in an RA patient who gets pregnant, their range was zero point six to four percent, and that seems to go along with a lot of national averages in developed countries. They showed no effects from these many studies on fertility in either men or women, and only one study looked at breast milk and found that it wasn't a factor. So, it seems colchicine and this is obviously going to be a problem with or not with gout, where the patients are older and not likely to be young females or women of childbearing potential, but instead would be auto inflammatory conditions and the like like these FMF patients.

A Journal of Rheumatology, a systematic review of sleep therapy in fibromyalgia, 47 trials or studies, 11,000 patients. The most significant, consistently significant, sleep intervention in fibromyalgia was wrong. It's cognitive behavioral therapy, the thing that we're really not doing in rheumatology. Yet the studies show, you know, overwhelmingly and consistently that it works in reducing pain. And in this case, it actually, was better at improving insomnia than it was at improving pain.

But there certainly are studies that prove the latter, though this study did not show improvement in pain. Other drugs that we often that are approved for use in fibromyalgia, pregabalin and sodium oxybate, had small effects, not important effects. That usual drugs, amitriptyline, milnacipran, Savela, duloxetine showed no benefit. So again, this is I tell my patients, you know, if you sleep bad, you feel bad. You're never going to feel great until you sleep great.

And once we improve your sleep, by whatever means, you're going to be 50 to 70% better. Everything else we use, those drugs I just mentioned for pain or fibromyalgia management, again, they're useless until you control sleep. So that's my advice. J and J had two announcements this week. FDA granted, nipocalimab, the, neonatal Fc receptor, antibody, a fast track designation for its studies of nipocalimab in moderate to severe Sjogren's disease.

We did report on that at ACR. That was kind of one of the big reports coming out of ACR twenty twenty four. But now they're moving ahead with development of that. They also had an announcement yesterday that the FDA approved their IL-twenty three drug, besilcomab, as both a sub q and IV therapy for patients with problematic Crohn's disease. Crohn's disease.

An Ontario study in the Journal of JAMA Dermatology looked at serious infection rates, and we don't often get serious infection rate numbers on common drugs. They looked at it in patients who were taking biologics and targeted synthetics. And what they showed was a very low rate and significantly lower numbers of SIEs. These are hospitalizable serious infections in psoriasis patients taking IL-twelve, IL-twenty three and IL-seventeen inhibitors. These rates were often thirty five percent lower than some of their comparators.

I want to say the rates were like roughly around two SIEs per one hundred patient years. Other drugs that are commonly used methotrexate, other DMARDs, other non TNF biologics were not increased but not decreased. And maybe a surprising thing here was that JAK inhibitors were significantly increased with a, like I guess it was an odds ratio, almost three or a threefold higher risk of SIEs. So how do you make sense of this data? You know, do biologics cause serious infection?

I said no. I say it's inflammation that causes that. If you are using the biologic in the worst possible patient, yeah, the biologic might contribute to risk. We do know that when you compare SIE rates of biologics used in psoriasis versus biologics used in RA, RA in Crohn's disease is much dirtier, and they have higher SIE rates four to five to six per one hundred patient years. Whereas psoriasis, it's much lower, like around two and less than two.

And that's what they're seeing with IL-twelve, twenty three and seventeen. Which, by the way, in the world of dermatology are the hot drugs. Those are the class leaders in therapy, giving you posse 100s and total clearing number. They use them earlier. When you use the drug earlier, you're going to have the lowest possible SIE rates.

So it's really when they're probably and again, this is not discussed in the paper, but this is my interpretation of the data When they use other drugs which they don't use all that much, like methotrexate and other DMARDs, and then in dermatology they're very afraid to use JAK inhibitors, based on the oral surveillance studies. TNF inhibitors are not high on the list, so they get used later. So they don't do as well or have a much lower SIE rate. Or in the case of JAK inhibitors, where they're getting reserving until, you know, they run out of options and patients are not doing well, I'm not surprised they see a threefold higher risk. Do I believe these risks that I've just portrayed to you from this JAMA Derm article are uniquely tied to each of the drugs as I mentioned it?

No. It's uniquely tied to how you use these drugs, and when you use these drugs, and who you use these drugs. Another important study came out this week on emphasis related arthritis patients. As you know, this is one of the JIA subsets. This is a study of 26 kids that became adults.

So they enrolled them as usually older kids around the median age, or mean age was 12. And then they did a follow-up on them before age 35. I think the mean follow-up age was around 20 years of age. These were seventy seven percent male, almost sixty percent B27 positive. And when they looked at them, most of them, when they looked at them as adults, they were in remission or low disease activity state, but twenty percent still had synovitis or enthesitis.

Seventy three percent had evidence of SI damage, fifteen percent hip damage, and eight percent spinal damage. So, during their early years and in the course of their illness, they do incur problems. Maybe when they get around to being an adult, maybe only twenty percent still have problems, but they do still have damage. And that's what may happen when those ERA patients show up in your adult rheumatology clinic. I came across an article this week about the alpha gal syndrome.

As you know, this is a tick borne allergy, where patients that are bit usually by the lone star tick develop a, you know, IgE response, an allergy to galactose alpha-thirteen galactose or alpha gal. They get, after they eat meat, mammalian meat and sometimes some other products, they develop hives, itching, swelling, GI complaints, rarely anaphylaxis, although it's been reported. And they get symptoms usually two to eight hours after their exposure to meat or ingesting of meat. Again, it's rarely life threatening. The point of this particular paper was that when this was introduced back in 2009, you know, time to diagnosis was often like five years or more.

And now it's dropped to less than a year in a lot of the studies, and the most recent number was at twenty five percent. Diagnosis is made within the first month of them developing these symptoms. These are symptoms that you do develop because of that sequence of the tick borne bite, and then subsequently eating mammalian meat. Because of the crazy way these patients present, I think it's important to review here. You may see these patients.

JAMA had an important article at the beginning of the week about mezorabine in patients with lupus nephritis. This was a Chinese study, a multi center prospective open label phase three trial of lupus patients who had either class three, four or five, or combinations thereof of lupus nephritis, with at least one gram of protein on twenty four hour protein testing and a SLEED eye of eight. The patients were randomized, but treated in an open label fashion, to either IV cyclophosphamide or oral, Mizorabin, which is given as a TID oral drug. Mizorabin is a drug that's a purine synthesis inhibitor. It's kind of similar to mycophenolate, if you will, or azathioprine.

It's FDA approved in Japan for lupus nephritis, rheumatoid arthritis, and some cases of nephrotic syndrome. It's not approved by the EMA for use in Europe. It's not approved in The United States. But this kind of result and publication in JAMA may lead to seeing it in the future. The primary endpoint in that trial was a complete remission rate, renal remission, after fifty two weeks.

So their total remission rate was complete renal remissions plus partial remissions at fifty two weeks. Two forty three patients treated for a year, the mean age of around 34, eighty eight percent women. Mezorabine was non inferior to cyclophosphamide with a complete remission or a total remission rate of sixty six percent versus seventy seven percent. Those were not significantly different. They had similar rates of side effects, although actually there was more adverse events with mizorabine, although cyclophosphamide had a few more cases of leukopenia, like three percent versus one percent with mizorabine.

Anyway, it is important because it's an oral therapy that's out there. We might be seeing that in the future. Axial involvement in psoriatic arthritis was written about this week. A cohort of Greek patients, nine twenty two with psoriatic arthritis, when they reviewed those patients, twenty six percent had axial psoriatic arthritis. And that's about, you know, I've always been taught that it was twenty percent of the, whereas that's one of the five subtypes of psoriatic arthritis, about twenty percent.

And the question is, it's important to note who these people are because certainly all of our psoriatic arthritis drugs will work there from methotrexate to TNF to IL-17s, IL-23s, IL-1223s, JAK inhibitors, etc, right? But the issue is that they have axial disease, they won't respond to twenty three because IL-twenty three inhibitors don't work in spondylitis. Well, as you know, Philip Meiss raised that question and is studying that issue and lectured about it in our twenty twenty four RheumNow Live meeting, where there is some preliminary data on the use of IL-twenty three inhibitors showing some efficacy in axial PSA patients. Anyway, in this twenty six percent of patients who had axial PSA, they were less likely to have peripheral arthritis at diagnosis. They had more B27 and emphacitis and inflammatory bowel disease.

Forty two percent of this cohort, of this two thirty eight, had isolated SI disease, and that was more likely in those who were younger and those who had enthesitis. A third of them had isolated spinal disease without SI involvement, and a third of them had non radiographic axial SpA, and those were more likely to be females, and also younger compared to the ones who had radiographic axial spondyloarthritis. That's the profile. Look for them, know how to treat them, watch out for new research on what is the effective therapies there. Two more reports: disease activity during pregnancy in rheumatoid arthritis and spondyloarthritis.

This was a nice report from BMC Rheumatology. 01/2024 women who either had rheumatoid arthritis and or not and or spondyloarthritis. And they follow them, fifty three RA, seventy one SPA patients. And it basically showed that these pregnant inflammatory arthritis patients did very well and had stable disease activity in their first, second and third trimester. However, there's always that however, a third of the RA patients had a disease relapse during pregnancy.

Thirty nine percent had a relapse during SPA. And roughly about a quarter of these patients required intensification of treatment, meaning use of more advanced therapies, Or going back on previous therapies. Thirty five percent of RA patients received the TNF inhibitor, and sixty two percent of the SPA patients received the TNF inhibitor, again during pregnancy. The predictors of disease relapse, or we talked about before, being nulliparous gave a six point five higher rate of relapse. And having an RA flare in the prior twelve months to conception also seemed to increase risk.

An interesting article this week from Forbes about the role of nurse practitioners and physician assistants or advanced practice providers in The United States. I thought it was really important to put up there. I think you really should look at it. The number of physicians in The United States is below the worldwide average. We have a physician shortage, especially in primary care, and it needs to be addressed.

And you know what? It's being addressed by the growth and incorporation of APPs into practice. NPs and PA programs started in 1965, and I'd say that their use in health care has exploded. Right now in The United States, there's 280,000 nurse practitioners, 145,000 PAs. I get a lot of people asking me to write letters of recommendation to get them into PA school.

I'm more likely to get someone into medical school than I am to get someone into physician assistant school, which is really hard to get into. But it's exploding, and right now this large cohort of health care providers are throughout all of health care, including in rheumatology. Right now, it's estimated that they make up one third of the clinical workforce in The United States. They provide at least 25% of all health care visits in The United States, and that they are one of the fastest growing professions. The argument or the discussion in the paper in Forbes written by a gastroenterologist is that he says, In my experience, most NPs and PAs are, you know, good to great, but some are not.

But he also says the same is true of the physicians he works with. And I think that that's pretty accurate. And then the argument is why I mean, do they they get different training, obviously, doctors and NPs and PAs. But actually, when it comes to outcomes, APP cared for patients do just as well as MD cared for patients. And the question is, should they be trained differently?

You know, we have overlapping scopes of care. And the question is, how are you going to train these folks? And right now, that's really lacking. Most of the APPs in rheumatology have entered rheumatology without any formal training, and you don't have a curriculum for them. Good news: the ACR does have a curriculum for them.

It's $2,400 that they have to pay for. And belonging to RAP, they've got an intensive, CMB program, to train APPs in all areas of rheumatology, so I would encourage that. Let's go back and, let's end with a few cases that I thought were interesting this week. One from Doctor. James Udell, a rheumatologist in Pennsylvania.

He sent me an email initially asking me how often I test for hepatitis B and RA, and my response was, Just once, unless the risk changes. And then he says, Well, you know, maybe we should be doing it more frequently like we do TB. And I say, Nope. The rule for me is I test once for TB, and I retest when risk changes. And he said, well, you know, actually he didn't say it.

I said, I know that insurance programs often ask you to get that annually, or and I know that the dermatology guidelines say that you should do TB testing, you know, annually. Wrong. It makes no sense. It's not needed. And that's what the TB mavens will tell you.

He has a patient who was Hep B, Hep C negative in 2010. Core antibody was not done. And more recently, while the patient's doing well on methotrexate infliximab, the patient, I guess after traveling internationally to Cameroon, now has a positive Hep B. And, you know, consultants have said this may be a reawakening of old Hep B. Again, it's not reawakening of old Hep B if he was, you know, we don't know what the core antibody was, right?

We don't know what the, so that's possible it could have been reawakening. But obviously this is going to be acute new infection if the patient is B surface antigen positive, right? And if the patient is B surface antigen positive, you're gonna have to stop methotrexate and infliximab, get a hepatologist involved, and start the patient on antiviral therapy. And after the patient has been on a few weeks of that, you can probably start back on some therapy, not methotrexate, and probably not high dose infliximab. So, again, my rules here are: again, test at the start of therapy, and then if risk changes.

So, what I wrote down is: again, stop the methotrexate, hold the infliximab, use another biologic. What could you use once this patient starts treatment if they have active TB? The safe drugs on my list are gold, hydroxychloroquine, nonsteroidals, prednisone five to ten milligrams, and anakinra. After the patient's been on therapy for a while, I would go ahead and start a JAK inhibitor or an IL-six inhibitor. I would probably not, and you should definitely not, use rituximab or high dose infliximab, and probably not abetacip right away.

But those are the options. I hope you find that interesting. I did. I received a call this week also on an interesting case of maybe Still's disease. This is from Doctor.

Mary Guany from NYU. Mary, I hope I got your last name right. G U A N E. Mary's a fellow there and had a great case, and she asks, she says, what would I do to treat a problematic Still's patient, 42 year old woman who has nine months of FUO, weight loss, fatigue, cytopenias, anemia, and thrombocytopenia, splenomegaly, sore throat, wrist synovitis, a ferritin up to 33,000, IL-two receptor levels of 2,100, non diagnostic bone marrow biopsy, skin biopsy, and thought to have basically secondary macrophage activation syndrome. The patient has had elevated LFTs, did have a normal CPK, and did have a elevated aldolase of 12.

The problem was the patient was controlled initially with high dose steroids, and then anakinra, and then anakinra one hundred milligrams TID. And then that seemed to lose effect, or be only partial effect. More steroids, changed to tocilizumab, which partial response, again more steroids. Patient was even tried on a higher dose of a JAK inhibitor, still not responding. And the question is: How do you treat this refractory case of Still's disease?

And my response is: I doubt your patient has Still's disease. And why am I saying that? Well, she doesn't meet Cush criteria, which are major and minor criteria. Major criteria two, minor criteria one. You get two points each for the following: Seronegativity, the quotidian fever of greater than 102, the rheumatoid rash, simultaneous elevation of white count and acute phase reactant, usually CRP or sed rate, And lastly, Carpal Echolosis.

You have all five, you got 10 points, you got the diagnosis. 10 points for diagnosis. You get one point for age less than 35. Polyarthritis, not monarchitis, not polyarthralgia. Polyarthritis, RA like polyarthritis.

Serositis. RES involvement, that's reticuloendothelial involvement, by that I mean hepatomegaly, splenomegaly, or elevated LFTs. And then lastly, either cervical ankylosis or tarsal ankylosis or tarsal arthritis. You do the math on this case, there's seven points. In my opinion, in my experience, they don't come close.

I'm sure this patient would meet Yamaguchi criteria, and I think Yamaguchi criteria are good. Their sensitivity is good, the specificity isn't as good. The Cush criteria have better specificity. You have to take my word for that. So what would I do in this?

Again, she doesn't get the diagnosis because she's never had serositis, ankle arthritis, an RA like polyarthritis. Don't you don't get any points or credit for very high ferritins. Hyperferonemia is only seen in fifty percent of patients with stills. Ninety percent will have an elevated, highly, a very high sed rate or CRP, right? So that's what you really need to look for.

So, you don't get points for ferritin or fatigue or weight loss or cytopenia. Cytopenia is immediately a big red flag. That's either an incredibly bad case of stills with MAS or another diagnosis. The patient has a lot of GI symptoms, and the patient has not responded to therapies that usually work in stills. So I suggest that since this is an adult onset acquired autoinflammatory or febrile disorder, that number one, you need to consider Schnitzler syndrome and do an SPEP looking for either a monoclonal or oligoclonal gumopathy.

And that would help to affirm that diagnosis. I said you should do CPK and aldolase. CPK should be normal. Aldolase is elevated, not inflammatory syndrome. And Still's, this patient did have basically those findings.

I think that when you don't meet criteria for Still's, you're obligated to do gene testing. And that means either sending off a gene screen for autoinflammatory diseases to invitae.com, have the patient pay for it, you draw the blood, it'll be $150, you'll get 85 genes tested for. That's one way. Really, what the pediatric rheumatologists are doing these days is whole genome sequencing, which will get you the same amount of data to find out what the patient has. And I said, if you can go where the money is, go where the money is.

There's a liver problem and a GI problem here. I would run the GI tract either with a scope or a camera study, and I would biopsy the liver pending the results of the gene screens. And that's how I would approach this patient with what has what seems to have an autoinflammatory syndrome, but yet undiagnosed. And I reminded Mary that the world's best center for auto inflammatory disease management and diagnosis is the NIH Auto Inflammatory Clinic run by Raffaella Golbakmanski and Dan Kastner. And John Hausman, who does the ACR On Air podcast, reminded me a few years ago that sixty percent of their patients don't yet have a diagnosis.

So don't feel bad if you don't always get a diagnosis. And when you don't have a diagnosis, treat it just like you would overlap syndrome. Treat their manifestations. It's a little more obviously than symptomatic management. I recommended that the patient go on methotrexate, hydroxychloroquine, steroids, and probably either use canakinumab or consider using IV tocilizumab in a higher dose, or changing the JAK inhibitor that you used.

And you might have to use higher. So we'll wait for the results of that. And if we find out from Mary an alternative diagnosis, I'll update you in the future. Wow, a really long podcast this week. Thirty minutes, shame on me.

But I hope you had a long drive or a long run or had to listen to me three times, scratchy throat and all. We'll see you next week.