TNR Grand Rounds - Evaluation Of Febrile Rheumatic Patients Part 2 Save

Go to the Q and A part of our lecture. Don't touch the front of your mask. Thank you very much. That's absolutely true. I have a problem with this face in many ways.

Sick COVID-nineteen patients also seem to get masks. That's absolutely true. I believe this cytokine storm everyone's talking about really is inflammasome activation, which is why the IL-six inhibitors work, which is why there are a number of trials going on right now, using IL-one inhibitors as well. And so this really is macrophage activation syndrome, which is important because you, the rheumatologist, may be called into service when they don't know what else to do. And again, what else do you do?

IL-one inhibition, IL-six inhibition, emapalumab, look it up. It's important. I'm gonna put some of these slides up, as downloads, if you wanna, download the slides and have them as a reference. What else do you use after those? I would use a JAK inhibitor, probably tofacitinib, because I've seen data about tofacitinib and its ability to inhibit, the interferon, especially gamma interferon, which is probably why, some JAK inhibitors have a high rate of zoster infections and others may be less.

That might be a backup therapy in addition to etoposide. In patients with masks that are very sick in the ICU, has anyone given etoposide and anakinra together? I've not seen it. I don't think you need to do it. I think etoposide's a more slow acting medicine.

Anakinra, a more fast acting medicine. Obviously, I favor anakinra. I'm not a hematologist. When you call in the hematologist, that's what they're gonna write for. Everyone else is either doing cyclosporine, a calcineurin inhibitor, or when a rheumatologist gets involved, we're going to do IL-one, IL-six, now, Gamafant or Emepalumab.

Is Still's disease antigen driven or is it auto inflammatory? It clearly looks to me to be auto inflammatory. There's very little evidence of it being an antigen driven process. It doesn't have any auto antibodies associated with it. It meets many of the characteristics seen in all of the other auto inflammatory syndromes.

Richard, I struggled with this question for many years, and I truly firmly believe it belongs in the auto inflammatory category. However, if that is true, then why is there not a gene? Well, partly because this is an acquired disorder. And most of the genetic monogenic disorders are there almost constitutively from birth or early in life. And I think that it's possible to have an acquired auto inflammatory disorder.

I mean, that's what we see in gout and Behcet's and sarcoid and even Blau syndrome, Blau's being genetic. Many of these developing even in adulthood. David Knapp from Tennessee says that a patient with clinical stills, who does meet full criteria is occult malignancy or infection or TB, a consideration that requires invasive testing, like bone marrow biopsy or tissue biopsies. Really good question. I think that this day and age, you're more likely to get a consult and someone who's been fully worked up, as opposed to coming to you de novo where you hospitalize them and you do the workup.

Often they've been seen by ID and a hospitalist and maybe even other services and not uncommonly drives us crazy when we get called last to the table and people are futzing around not making a diagnosis that you can make in your sleep. So often that is done. I would say a bone marrow, biopsy and or aspirate could be a very important part of an FUO workup if all cultures prove negative, and it doesn't look like an auto inflammatory or Still's disease diagnosis. I would consider that and or a blind muscle biopsy in some people, but I also am more likely to make the diagnosis if the patient meets criteria, then we can safely move forward. Criteria do by the way, say, you must have been worked up sufficiently and had infection and malignancy ruled out in those cases.

Can you tell me more about traps? You know, it used to be called Hibernian fever. It is sort of, European descent individuals. Fevers can last as little as seven days and, usually, but it's more like two to three weeks. There is a periodicity, they get a lot of the same features that you get with the other auto inflammatory syndromes, which includes fever, and rashes and crazy looking labs and systemic, manifestations, like many of the auto inflammatory syndromes, they also get a propensity to get secondary amyloidosis.

Can be systemic amyloidosis or renal amyloidosis, and we know we say that amyloidosis commonly occurs on the other side of the pond in Europe and in The UK and in Israel, not so much over here. Well, I've seen a lot of Still's patients. I've had two of my patients die with renal failure and renal amyloidosis. So amyloidosis occurs in the cryopyranopathies, CAPS, Muckle Wells. It also occurs in TRAPS and many of the auto inflammatory syndromes.

What's your experience with IVIG and mass cytokine storm? I have none. I've seen some reports. I think it reflects frustration more than anything else. I'm frustrated by use of IVIG.

It's to me a bit voodoo late in the game, and I like to know a little bit more about what I'm doing and why I'm doing it, yet there may be a good role for IVIG where? In refractory inflammatory myositis, and I'll say in early skin, progressive systemic sclerosis. There's some trials going on in that. And there's a few others obviously that many of you have known about. I missed this, but how does the rate of thrombotic events fit with mass vis a vis COVID or stills?

Thrombotic events are not typical in stills, DIC, sometimes with thrombotic events have been described rarely with hemorrhagic events. I did describe this week a report, actually I didn't describe it, New England Journal described in a correspondence report of three cases of patients with thrombotic CNS lesions that were hemorrhagic and associated with IgA anticardiolipin antibodies and IgG beta-two glycoprotein-one antibodies. And these patients had encephalopathy and neurologic deficits. Does thrombotic events occur with mass? It's not high on the list, but I'm sure it occurs, I just haven't seen it that often.

Next, would you consider a patient with intermittent fever for a few years and not daily fevers for genetic testing? If truly is intermittent fevers and it fits that pattern of either three days of fever, seven days of fever, or fourteen to twenty one days, and then they go into disease free intervals, then yes, I would do genetic testing. I gotta tell you, I see a lot of Still's disease consults. I might see 20 a year. I've probably seen hundreds in my career.

And the number one Still's disease referral that I see is someone who thinks they have a fever when they really have fibromyalgia and they tell me that their fever is a 100. That's not a fever. We're talking about a fever greater than 101, is would be my cutoff for consideration of genetic testing. Acthar Gel, not unless you put a gun to my head and I still would not do it. It's voodoo, it's not approved for anything.

Well, it's approved for some things, it's not been tested in anything. The company should do trials in diseases, it wants to sell the drug. It's way too expensive, it bankrupted Rockford, Illinois. If you ask about Acthar Gel, I'm sorry, you get the brutal honest truth, it's criminal to use it in this situation. All the other steroids work, why would you use the most expensive one?

What about Ilaris instead of Anakinra? Really good question from John Tesser. John, how are you buddy? John, you should be giving these lectures. I'm gonna call you, you're gonna give one of these lectures.

Ilaris and anakinra, I think it's a very good choice. I think the benefit of anakinra is its weakness. It has a short half life. It's got a half life of six hours. So if you're treating Still's disease, you gotta give the drug at night, don't give it in the daytime.

And if they're not responding, double the dose, especially to a big person. But the problem is the short half life, but it also works fast. Almost everybody's gonna respond to IL-one ambition will probably respond, in the first day or two, if not the first shot. The longer acting, canakinumab may take a few days to really get a response, but it may be the better drug in the long run. So I am currently starting out with people in the hospital for new onset severely active systemic disease.

I'll give them anakinra. It's easy to get in the hospital, by the way. It's hard to get as an outpatient, as you well know. But then once they've been on daily injections with anakinra, then I would probably switch them over to a longer acting, agent, and, EYLARIS would be a good choice. Now, right now there is no drug that's approved for adult Still's disease, that's an IL-one inhibitor.

The IL-six inhibitor is approved, the IL-one inhibitor canakinumab, and I guess there's another one, that they are approved in kids over the age of two with systemic onset disease. I use that wording to try to get my IL-one inhibitor approved in my adult saying they have systemic onset JIA, it just happens to be an adult, and they are over the age of two. Meets all other criteria and then you send them, you know, a wad of papers this thick showing that it does work. They'd actually have to approve it. Andres Caseno asks, is methotrexate the first line medication for stills?

What about anakinra as first line? Well, that's a great question because you are either being prudent about your therapeutics and expenses, you know, prior to the availability of, and by the way, I wanna say TNF inhibitors are not to be used in acute systemic disease. They don't work, they don't work. Save your TNF inhibitors for management of RA, chronic inflammatory polyarthritis. But acute systemic disease, prior to biologics, the treatment was high dose steroids and they don't respond to 20, they need one to two milligrams per kilogram, that means forty, sixty, eighty milligrams a day, and methotrexate because you wanna do steroid sparing.

And that worked at about half the patients. So Andres, using methotrexate would not be a bad choice, The problem is you will expose them to a longer period of steroid use. Now, on the other hand, the use of an IL-one inhibitor is a quick empiric trial. It's sort of like one shot and boom, you have your answer as to whether or not this is an auto inflammatory diagnosis. Would methotrexate work in other auto inflammatory diagnoses?

Less commonly so. Would the IL-one work in stills and auto inflammatory diagnosis? More likely so. So anyway, very good question. I think these days, I'm probably using more Anakinra right out of the gate.

But I probably could easily use methotrexate if I were a situation where cost containment was important. Doctor. Abelis, I presented an abstract at the ACR, at the ACR indicated that PMR was rarely associated with fever. Well, that's true. It's not a common manifestation of it.

PMR, I would say is a seldom the cause of an FUO. GCA on the other hand, more commonly. So whenever I include GCA, temporal arteritis, I'll always throw in PMR because PMR patients may have a fever and you'll find plenty of reports in the literature saying PMR, presenting as an FUO. They're out there, but I agree that GCA, Temporateritis, is a more common cause of an FUO that could be still confused with Still's disease. And guess what?

They're gonna be old. Still's disease doesn't occur in people over the age of 65. They're gonna be white. Still's disease is in all races, all sexes, and is usually in much younger people. FB3.

You are a special person, FB1 or FB2. Do all COVID patients intubated, or should they be given a biologic? I think a COVID patient these days who ends up in the ICU is gonna get immediately put on antimalarial, either chloroquine or hydroxychloroquine. I think if they have widespread pulmonary manifestations or get intubated, I think they're quickly going on an IL-six inhibitor, if not in a study with an IL-one inhibitor. I know of a patient that they waited until the IL-six levels to come back before they started the tocilizumab.

Yet at presentation, the patient's CRP level was 500 milligrams per liter. It's gigantic, gigantic. And I said, wake up, where do you think the CRP is coming from? It's all IL-six. And yes, the patient did have tremendous IL-six levels and should have been given Actemra two days earlier, but nonetheless, I think that patient has done well.

Mr. Anonymous says, what are your thoughts about remdesivir and IL-six or IL-one inhibition together? Obviously not in Still's disease, you're lapsing into a corona discussion, but, I think all of those are experimental therapies. Let me go back to the previous question from one of my colleagues about the use of a biologic in patients in the ICU with pulmonary manifestation cytokine storm. If you get the corona infection and you don't have severe respiratory distress, you know how you're gonna be managed, you're not gonna be put on hydroxychloroquine.

You're gonna just stay home and you're gonna monitor your symptoms and treat symptoms symptomatically. ID specialists are not starting those patients on hydroxychloroquine or remdesivir or Actemra. So I think that these drugs are basically being used in the most severe cases, usually under direct observation hospital and or in ICU. That's talking about the coronavirus infected patients. Doctor Horvath, those with hyperferrit anemia, is there a certain level that's concerning?

When it's five to ten thousand or more, is Still's disease more likely than a malignancy or an iron overload situation? No, it is not. There's no number which Still's disease is more concerning. The higher the number, the more I'm concerned about macrophage activation syndrome. What's happening to their white count?

Is it dropping when it was high? What's happening to their platelet count? When it was high and now it's dropping. What's happening to the sed rate? It was high and now it's dropping.

The patient's looking worse, the lungs are looking worse, the liver's going down the toilet, it's MAS. I think again, ferritin is a great measure to use. It is not the biomarker for Still's. The Still's biomarker, are there symptoms, the key symptoms that we talked about? Aldolase levels, the neutrophil to lymphocyte ratio, sed rate and CRP?

Yes, sure, ferritin, but use ferritin as a tool about how much you're going to worry about the risk of MAS. IVIG might be useful for COVID associated ADE antibody dependent enhancement from neutralization antibodies would start. Yeah, but gene IVIG and COVID would be experimental and now we're trying to find a niche for it. I would not be recommending it as a rheumatologic consultant. You're welcome to, not me.

I'm not on that list. Doctor. Quinnette at the Oxnard Clinic, how are you Robert? Any evidence of heterozygosity for auto inflammatory genes in stills or systemic JIA? No, but it has been shown that patients diagnosed mainly with systemic JIA, when they do undergo genetic testing, can find a known auto inflammatory diagnosis and as much as I think ten to twenty percent of patients, mainly correcting the diagnosis.

I don't think it is heterozygous presentation of a known, genetic defect that is, leads to a more confused diagnosis of Still's disease. I think that, again, the more atypical the patient is, the more you should do genetic testing to confirm the diagnosis of systemic JIA in kids and adults. What's my first go to drug in Still's? It always depends, but steroids, eighty milligrams a day, sixty milligrams a day, IV Solu Medrol, forty BID if they're in the hospital. And then based on what's going on, you you could even use methotrexate and hydrosteroids in patients who have LFTs that are up to four or five times normal, because correcting inflammation will correct that.

Most people are afraid to do it when LFTs are that high. Most people with LFTs that high might use prednisolone over prednisone, because it's less metabolized by the liver. But again, my go to is high dose steroids and I probably would use more Anakinra as my first choice, especially in someone who is hospitalized. Let's see. So in a patient who has intermittent fevers for three days, but negative FMF testing and no other causes of fever, but has the right ethnicity, meaning of Mediterranean origin, would you consider colchicine trial?

Sure, it's easy, it's well tolerated, why not do it? I might even consider after that a trial of anakinra. The problem is that FMF, the attacks last one to three days. They can almost always be prevented by colchicine or treated with acute steroids rather than using an IL-one inhibitor or other agents to manage FMF. So I think that's certainly a smart thing to do, just based on the duration of the fever.

I use Ileris in one traps and one stills after anakinra. And yeah, it works after anakinra. And IL-one inhibition, actually the early data on traps was they didn't respond to infliximab, they do respond to etanercept. Guess what folks? They have way better responses.

I think fifty percent of them respond to TNF inhibition, and tantalcept, but like eighty, ninety percent respond to IL-one inhibition, either anakinra or canakinumab or rilanacept is the other one. Rilanacept just happens to be ungodly expensive at more than $250,000 for a year supply. A kanakinumab over a 100,000 is still quite expensive. And anakinra, don't know what the recent cost is, but it's probably closer to 60,000 a year for daily anakinra in someone who needs it. Blau syndrome, I'm not the expert, Burat.

I wish I could answer that for you, but, you're gonna have to read up on that. Maybe someday I'll write about it. What is the role of JAK inhibitors, if any, in STILs or systemic JIA? I would use them. I have used them to manage, MAS in someone who could get cyclosporine and or etoposide, and it worked really well.

I was able to stop the patient's IL-six inhibitor and continue them on methotrexate and JAK inhibitor and control their fevers and get them out of MAS. But again, this is experimental. I mean, are trials I think that people would like to do here. The problem is trials in systemic JIA and adult stills are very difficult to do because it still is a rare disease. As I said, there are twenty cases this year in Dallas.

How many am I gonna see in Dallas where all my friends here know I'm interested in this, know I'm the self declared expert. I might see one or two from the local community, which means that the vast majority of these cases are running out there, are out there under the care of many different people. So there may be a role for the JAK inhibitors. Will they all be the same? I don't think so, because I think the JAK inhibitors as you're going to see in the future, have a differential effect on gamma interferon in in vitro studies, or ex vivo studies, not in real life studies.

Again, I don't expect real life clinical trials to happen there. Let's see, a pulmonologist in the ICU task force, 73 recommended hydroxychloroquine when COVID, presented with pneumonia but not ARDS or CSS. I don't know what CSS is. Pneumonia but not ARDS, I'm sorry, there's a fine line between those two. It's not surprising, we're talking about severe patients.

Again, the patient who stays at home, is not getting hydroxychloroquine. If you look at our task force, I'm sorry, our town hall we had almost two weeks ago, we asked our experts, including two ID specialists, would they recommend patients go on hydroxychloroquine, Our patients go on hydroxychloroquine as prophylaxis. They all said no. They up in arms about the overblown effects or supposed effects of hydroxychloroquine? They all said yes.

But yet they all said in response to the question, would you take hydroxychloroquine if you got COVID? They all said yes. Mainly saying, well, it might help and I know it's safe and that's why they would use it. So there's a little bit of a paradox there. But again, I think we have to safeguard the stockpile of antimalarials for patients who really need them, and make those decisions on individual case by case basis.

I got time for maybe one more question. What about steroids? No, that's a Corona question. I'm gonna end there and thank you for your time and taking the time to view this presentation. Be sure to tune in for future lectures on Tuesday night.

I think we've got a cast of speakers who are really superb and I think you'll find those worthwhile. I'll post this in the next few days on the website. I'll try to post some slides that I can share for you as well. Have a good night, tune into RheumNow. Bye now.