Diagnosing Neuropsychiatric SLE (5.23.2025) Save

It's 05/23/2025, and this is the RheumNow podcast. Hi, I'm Doctor. Jack Cush, executive editor of roomnow.com. This week on the podcast, the vagus nerve steps up in RA, or does it? Yet another way of diagnosing neuropsychiatric SLE, and dare I, should I, would I throw a damper on the CAR T cell excitement?

But first

Great rheumatologists go to great rheumatology meetings. Now for the first time ever, RheumNow live on demand is available. We'll have more coming up after today's podcast. First,

let's talk about methotrexate. Methotrexate was the topic of a New England Journal report. That makes rheumatologists happy. Any We love methotrexate. Anything makes methotrexate.

What about when it's in pulmonary sarcoid? Are you just as interested? Well, you should be. I think sarcoid is a disease that rheumatologists should be managing. My experience is that many are managed by pulmonary, but I don't get that pulmonologists love managing sarcoid.

And maybe it's because of the drugs steroids and methotrexate and others. But anyway, there's a New England Journal report this week of an open label one hundred and thirty eight patient trial of patients with active pulmonary sarcoid who are untreated, who are randomized to receive either methotrexate or placebo, with the primary endpoint being twenty four weeks. And the study was designed as a non inferiority trial. Is methotrexate as good as prednisone as first line therapy in pulmonary sarcoid? And this study showed at week twenty four it was non inferior to placebo with a mean change in forced vital capacity of minus 6.7 versus minus 6.1, not significant within the margins of non inferiority.

So, that was why it's a New England Journal report, because historically I think patients are given high dose steroids and then it's decided about whether we use methotrexate second line, and maybe because it's more toxic. But this basically says it's actually as efficacious when used initially, and as far as toxicity not much difference, but the difference being not much difference numerically in side effects, but the profile is different with the drugs being different. With prednisone, more weight gain, more insomnia. With methotrexate, more fatigue, nausea and LFT elevation. Things we can deal with, but I think this is an important trial.

On the tails of this study was another systematic review and meta analysis looking at a number of drugs being used mainly biologics being used for sarcoidosis, mainly pulmonary sarcoidosis, and mainly the I think the big home run, if there was one, and I was always not sure about this, was that infliximab has modest efficacy for pulmonary sarcoidosis. And actually, that is kind of my opinion. I think that TNF inhibitors may not be great in pulmonary sarcoid. They are probably better at ocular sarcoid and arthritis sarcoid. And then in this meta analysis they did talk about limited evidence for the efficacy of adalimumab, tofacitinib, and I'm going to struggle with this, it's a drug that I don't know, Efzofitamab.

Efzofitamab. Efzofitamab. Efzofitamab. It's a neutrophilin or NRP-two targeted drug that NRP-two has been found in the lungs of patients with inflammatory disease, especially sarcoidosis. Efsafitimod has been studied in pulmonary sarcoidosis and in ILD associated with scleroderma, and the thought is that this drug, which is not yet approved anywhere, as I know, is down regulates myeloid activity and inflammation at those sites.

So there's limited evidence for these other biologics in sarcoidosis, and mainly around certain indications, certain sarcoid manifestations. So, there is hope, there is development in the area of sarcoidosis. One of my favorite areas to talk about, because it's such a difficult area, is the diagnosis of lupus cerebritis neuropsychiatric lupus. I'm hoping we can have something on that on the website before the end of lupus month is out, but I found this nice report about assessing neuropsychiatric lupus using new high-tech imaging. These are three Tesla three d contrast enhanced vessel wall imaging.

I'm not aware of this or where this is available, but it's obviously high-tech, it's three Tesla. I mean that's like 11 on the scale of sound, right? Let's dial it up to 11. It's better than 1.5 Tesla. So, this study they compared forty seven patients who had neuropsychiatric lupus by criteria to four against forty two against forty two, or maybe it was fifty two, lupus patients who did not have neuropsychiatric manifestations.

And they found in the study that intracranial vessel wall lesions were enhanced twice as commonly or a twofold increase in vessel wall positive lesions, in patients with sarcoidosis I'm sorry with neuropsychiatric lupus. The area under the curve was 0.78, the sensitivity 60%, specificity 80%. I like that specificity, although the population they tested it against is kind of small. But, you know, we're struggling to make a diagnosis of neuropsychiatric. They come in and they're crazy.

They come in and they're psychotic, having seizures, have cognitive dysfunction, have the worst headache they've ever had, and how do you know it's not other, disorders and whatnot? I've always taught, because forty years has taught me, and I worked at a center at Parkland and Dallas County Hospital where we had tons of lupus. I mean just tons. If a lupus patient gets admitted to the hospital, it's more likely they're admitted to the hospital for non lupus reasons, which is not the way the house staff thinks about it. They always think, oh, it must be lupus.

That infiltrate on chest x-ray must be lupus pneumonitis or alveolar hemorrhage. No, it's more likely a pneumonia, dude. But it's different with the brain and neuropsychiatric manifestations. If they're admitted to the hospital with potential neuropsychiatric, it's more likely to be neuropsychiatric than it is to be due to comorbidities like infection and, uremia and all the other things can or drugs that can affect brain function. But how do you diagnose it?

In my opinion, I'm giving you a mini lecture here now, it's a lymphocytic pleocytosis. And I don't really care about protein or glucose, because they're not really helpful. I do IgG index and q albumin, and those are helpful. The q albumin should be modestly elevated in about fifty percent, that's between nine and fifteen. The q albumin is a measure of blood brain barrier intactness, and it's mildly affected in lupus, but majorly affected in vascular events and meningitis.

So, instead of being of 11, it's a q q albumen of 45 or 112. That's not lupus cerebritis. And then the IgG index is elevated and then you have to make modifications to the IgG index depending on what the Q albumin is. It's complicated, but maybe an imaging test. All of you like to do imaging as a tool for diagnosing this.

Imaging's got problems with sensitivity and specificity. This imaging might be good. Let's move on. Infusion related reactions, injection site related reactions, a study from one center 1,800 patients showed that these occurred in about ten percent of individuals nine point seven percent. It was more likely, and I don't really get this associations, but it's out there, something they studied it, we got to look at it.

It's more likely that you get injection or infusion reactions if you're younger, if you have secondary Sjogren's, if you had prior leflunomide therapy What? And and then it was less common with other, drugs that you might use abatacept, tocilizumab and galimumab. So, what are the magnitude of associations here? If, for the things where it was positively associated, it was basically, either fifty percent or two hundred percent increased. For things where it's less common, aba, toci and galimumab, it went down like about sixty to seventy percent.

Interesting. So, that means most of the injection site reactions are going to be related to what? TNF inhibitors, right? That's mainly the big thing we're talking about, but it could be other infusions as well. You know about the data about vagal nerve stimulation that leads to improvement in RA, and it turns out that vagal nerve stimulation is involved in a reflex loop that basically leads to a decrease in inflammatory cytokines, mainly TNF, and that's why it couldn't be effective in inflammatory disorders.

The issue here however is when it was first studied, reported by Mark Genovese in an uncontrolled open label trial, it looked really exciting, it looked really good, but they were at the beginning of the technology as to how you stimulate the vagus nerve and that was a problem. When they went into a phase two trial it didn't look good at all. But they continue to work on the technology and the more recent trials look promising, but they're still only phase two in my opinion. This report looks at the sort of the converse issue. If vagal nerve stimulation is important in RA outcomes, what if you looked at populations that underwent vagotomy?

What? Knocking out the vagus nerve therefore might increase the risk of rheumatoid arthritis. So a Danish study of vagotomies between 1977 and 1995 looked at over 6,000 of these and they were either done as super selective vagotomies or truncal vagotomies. And what they found was that the truncal vagotomy was associated with significant increased risk of RA. The RA incidence went up, the odds ratio was two point six.

That's impressive. But super selective vagotomy was not significant. Oh my god, the vagus continues to, confuse us. The vagus confuses us. But I think we just need better studies.

But this is, I think, an interesting way of looking at the importance of vagal nerve and its stimulation or ablation in the risk of inflammatory disease. Still's disease, I found this interesting report about neutrophil alkaline phosphates activity. And you know the, neutrophil alkaline phosphates test has often been done to support a diagnosis of myeloid disorders and certain leukemias where it goes down. I'm going to remind you what the test is all about. It basically is a staining test of neutrophils from the patient, and they count up the neutrophils and they score the amount of alkaline phosphatase staining within the neutrophil.

Normally, normal neutrophil staining activity for alkaline phosphatase is about three plus, okay? Then they count up the number all the neutrophils and all the pluses and they give you a score. It goes down when you have a deficiency of neutrophils, and it goes down when you're delivering immature neutrophils to the periphery. So, it goes up with infection, it goes down with myeloid and certain leukemias. So in this study one hundred and forty one Still's patients were compared to patients with B cell lymphoma, lupus, anti phospholipid syndrome and controls.

And they found that neutrophil alkaline phosphatase activity correlated with systemic disease activity in Still's disease with a really strong r value of 0.71. That's a correlation coefficient. And then for other things it was kind of good, I mean it was significant, but the r the correlation coefficient went down to 0.59, 0.52 for CRP, absolute neutrophil count, ferritin levels, and there were a few others. But the interesting thing here is that in Still's patients who did not have MAS, and before they had MAS, the NAP neutrophil alkaline phosphatase, activity level was high, very high. But with the onset of MAS it went low, and that's because you get that flip of leukocytosis to leukopenia, and you you get immature neutrophils being delivered into the system.

Anyway, this seems exciting however, NAP activity is elevating a lot of things. So whether it's really important in stills, which may be hard to diagnose is hard to know, but this is a test that you can order. You look at it, let me know what you find. There was a nice review article on therapies targeting the NLRP inflammasome, which is a, you know, basically the key driver to the initial innate immune response that delivers an abundance of IL-one and IL-eighteen. It's seen in Still's disease, it's seen in other autoinflammatory conditions, also gout, neurodegenerative disorders, it goes on and on.

Hence, targeting and treating inflammatory disease by targeting NLRP3 is great. There are a number of drugs that are in trials, many of them have failed for toxicities, mainly liver toxicities and others, but there's a few that are still out there, actually many that are being developed, including ones to oxidize DNA, which probably acts as a DAMP, a damage associated molecular pattern that activates NLRP3 and then leads to IL-one, and if you can target a DAMP or a PAMP, a pathogen associated molecular pattern, maybe that will down regulate the inflammasome activity and lessen IL-one and IL-eighteen, and curb the inflammatory response. Interesting way of approaching it look for it in the future. CAR T cell is out there. There's a nice review article that I published so that you can if all those of you who are CAR T cell enthusiasts can go wild with it.

But I put it up there to make the point that there are over 85 current therapeutic candidates that are in this class of cellular targeted therapies and cellular depletion. 85 of them in over three eighty clinical trials. What? Things have gone wild since Gaylord Schitt's fabulous report about initially was it nine and then 15 mostly lupus patients with great long term follow-up, great, you know, studies. I love that research.

I'm encouraged by that research, but I'm gonna throw a damper on it, because that's the only data we really have. So far we have lots of plans, lots of talk, lots of difficulty enrolling patients in these trials. They're all doing different things, and they're doing it maybe in different ways. And I just want to remind you that CAR T cell therapy, which has been very effective in the cancer world, is also very dangerous. Now, of course, we're talking about cancer patients who have high morbidity, high mortality, and adverse event rates in that population for any drug that you use is going be very high.

But last year the FDA issued a warning about, you know, mortality risk associated with CAR T cell therapies. And, and I think to expect that we're going to get magical responses and put people in remission with off drug after CAR T cell without significant risks, I think is a pipe dream. I think you got to wait on the data. We've talked about a lot of studies in lupus for instance that look great in in early studies and even in phase two. And then how many of them have made it past phase three?

I mean, again, these disorders are really hard to manage and these aggressive therapies, while promising, need to be tested in phase three. We're waiting for that. Talking about autoimmune vitiligo affects up to two percent of the population globally, more in blacks and Hispanics than white, more in women than in men. The prevalence has increased in vitiligo over time and adds to that increasing prevalence of autoimmune disease in society. Nice review article we posted for you says that steroids are most frequently prescribed.

Didn't think that they worked in vitiligo, but it turns out there's data about one that's used early that they have a role. But there's a lot of other therapies that have been tried in vitiligo, most of which have not looked great, but if you want are interested in this, look at that report. Periprosthetic, femoral fractures are a complication of hip replacement, and a meta analysis of 36 studies found that when these occur they're more likely to occur with uncemented stems, when the surgery is done at major teaching hospitals, more so in females and the obese, more so with high comorbidities, more so in RA, and also with revision THRs. It turns out that osteoarthritis was somewhat protective, lowered the risk of periprosthetic femoral fractures by forty nine percent. Two more reports, I think a nice report from JAMA from China, tocilizumab versus methotrexate.

In fact, it's modeled after an old Amgen trial: methotrexate placebo versus tocilizumab placebo versus tocilizumab plus methotrexate three arms. And patients were three forty adult RA patients, were treated, and these patients, I think it was like thirty percent of them, had previously received, conventional DMARDs. Some had received methotrexate, so that kind of screws up the analysis here. But nonetheless they were randomized to either tocilizumab once weekly, methotrexate ten to twenty five orally once weekly, then the combination given as you would expect. And in the end the methotrexate placebo response was twenty five percent.

The tocilizumab methotrexate response was fifty three percent, and the tocilizumab placebo response was fifty. So, both tocilizumab arms were better than methotrexate monotherapy. Tocilizumab monotherapy was better than methotrexate monotherapy. You could look at some of these graphs and say, gee, it looked like the combination was a little bit better, but they were not significantly different from each other, and the primary endpoint in this trial was an ACR20 response. They did show in patients who achieved a low disease activity state and they stayed on their therapy that they maintained that therapy out to forty eight weeks.

And the ones who weren't doing well, who flipped over to the combination, they did well out to forty eight weeks. So, again, I think this strengthens your thinking about how you use tocilizumab. It still is probably one of the better drugs we use as a monotherapy biologic, and I'm not a big fan of monotherapy biologics. Why would you do that when you get the boost and benefit of methotrexate? What was the side effects on this?

It turns out that any placebo monotherapy regimen actually had less of the serious adverse events than did the combination. I thought that was an And in fact maybe the lowest amount was seen with methotrexate, placebo compared to the other arms. I thought that was interesting. The last report is about pregnancy and autoimmune disease. I like this for the sheer numbers of it.

We sometimes struggle with what to do with the patients who want to get pregnant and should get pregnant. I would refer you to the great guidelines from the ACR, Lisa Samaritan, a lead author, published a few years ago. This is a claims data analysis of over six thousand pregnant women with autoimmune disease who also received a biologic during pregnancy, at least one dose. This includes Crohn's, RA, ulcerative colitis, psoriasis lupus, MS, and ankylosing spondylitis. The vast majority of patients, over half of them, had Crohn's and RA and ulcerative colitis.

And in this ten year study there was a gradual but significant increase in the use of biologics from 2011 to 2021, reflecting your increasing confidence in their safety in the setting of pregnancy in your patients. Again, the number went up from sixty four percent in 2011 to, seventy five percent in 2021. That was significant. The biggest drug being used of course is TNF inhibitors, and looks like TNF inhibitors did not change very much during the trimesters. It stayed basically around 80%.

Other biologics: Vedolizumab, Avatacep, Nadalizumab, Balunimab showed increasing use from two point three percent in 2011 to fourteen percent in 2021. But it was clear that across the board whatever biologic was being used it went down by trimester. As gestation went on your use went down. So in almost three thousand patients sixty nine percent were using a biologic in the first trimester, fifty nine percent in the second trimester, and forty nine percent in the third trimester. And then it bounced back up postpartum up to seventy seven percent, suggesting that either you're afraid to use them or you're not wanting to use them.

We do know that in the GI world with inflammatory bowel disease you keep the biologic going. And I would say the same thing is true for me in my patients. If I start out on the biological pregnancy, I'm continuing it. I want the patient in remission throughout the whole pregnancy, and that is the way to go, and I think some of these data reflect that it stays up in use in IBD and may go down with maybe an audience that's less familiar or less confident about the safety of biologics in rheumatic patients. And I'm telling you, you probably should be confident and follow the lead of the gastroenterologists.

I want to remind you next week is our final week of the Lupus Unlocked campaign, where we're covering all things lupus, and we have another Tuesday night rheumatology. Last week was a great one. I mean last week we discussed antiphospholipid, You really want to look at that. We had three discussants in there, Cassie Sims from Duke, Shruti Chatterveti from, a hematologist from Hopkins, and Jason Knight from University of Michigan. We covered a lot of ground, great discussion.

It's a good listen, and I would encourage you. Next week, it's gonna be pregnancy and lupus, where we're going to have Megan Claus, Lisa Samaritano, and Jill Bullion. That should be a lively discussion. Be there. Take care of yourselves.

Bye.

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