Autoinflammatory Still's Disease Panel - EULAR2020 Save

Hi everybody, I'm Jack Cush with RheumNow. Welcome to the auto inflammatory disease, AKA Still's disease panel. I'm joined by three experts and friends, all from New York, my home state. Doctor. Petros Athermio in New York City, Doctor.

Olga Petrina in New York City, and Doctor. Apostolos Concius out in Long Island. How's everybody this evening?

Very well.

Very good. Doing great.

Okay, so we're gonna I'm gonna turn this over to Petros and he's gonna talk about abstract Friday April. Petros, tell us about this, the IL-one inhibitor canakinumab for refractory Still's disease.

Yes, Jack. This is a retrospective longitudinal multicenter study from Greece, my home country, and it involved fifty patients with Still's disease, thirty nine with adult onset and eleven with systemic GIA and these were refractory patients and it followed them longitudinally and it was a successful study. By month one the majority of the patients had a response, it's a fast acting drug, and by month three there was significant improvement with the exception of one refractory patient. So this study was one of the largest cohorts of canakinumab in Stills disease and it showed efficacy doses one hundred and fifty to three hundred milligrams every four or every eight weeks. There were some interesting points from this study, for example if a patient had failed more than two biologics prior to studying anakinumab, it was unlikely they would achieve complete remission.

It also showed that patients with Still's disease tolerated well kinequila. The major side effects were infections, twenty percent, four percent of them were serious infections and six percent had leukopenia.

So the interesting thing I see in the paper is that, twenty four, of the patients had previously received an Akhinra and then moved on to another IL-one inhibitor. So that's kind of interesting. I think that's something people would know. Olga Apostolos, do you do that in your patients? Do you start out with one and go to another IL-one inhibitor?

I do actually use multiple IL-1s in my patients, mostly because we don't have that many effective treatment options available for them. So even if the patient fails one IL-one, I still give it a try with another one. And I feel like in a lot of my patients who fail shorter acting IL-one inhibitors, switching to longer acting one may make a difference and they can actually still have a good response.

I do the same, Jack. I do the same for a couple of reasons. One being that the short acting like anakinra, for example, is a daily injection. Many patients do appreciate that they have side effects from that injection side reactions more so than the longer acting ones in my experience. And the other thing is, especially the systemic onset early on robust inflammatory phenotype of certain patients.

I do think that higher doses of anakinra sometimes are required perhaps. And the longer acting ones like anakinlamide, for example, even at a dose of one hundred fifty or three hundred milligrams at times can do the trick sometimes in these high inflammatory patients to begin with.

So the other patients who fail, I would say not surprisingly, were people who are on steroids or methotrexate, thirteen had been on a TNF inhibitor, two had been on abatacept. These are not drugs that are really known to be very effective and especially systemic disease. So it makes sense to move on to an IL-one inhibitor in those. Is there was there anything from the abstract Petros about those people and maybe why would someone use those drugs as opposed to going right to an IL-one or an IL-six inhibitor? In fact, there were seven patients who had failed IL-six blockade before getting kanekinumab.

Absolutely and there have been acute case reports in the literature and of course, you know, the initial biologic use in skills were TNF inhibitors. I agree with you, it may work a little bit for the arthritis especially in the chronic articular phase but during the systemic phase they're less effective than IL-one, IL-six inhibitors so the choice of going to IL-one or IL-six these days more organically embedded in our approach but I think many some patients may have been falsely diagnosed with seronegative array that's something we see in the chronic particular phase and maybe through those drugs or it could be the level of comfort from physicians but I think the message is out there, it's definitely there for our pediatric colleagues and also for adults that the pivotal cytokines are L1 and L6. I thought it was interesting that in these abstracts that they were able to wean corticosteroids in fifty one percent of patients that's pretty similar to what Fabrizio DeBenademi presented in the oral session and across the studies both for tocilizumab and canakinumab even in the pediatric population it's pretty similar fifty percent of patients will come off steroids completely but the other fifty percent will not.

Does anybody want to take a stab as to how you choose between one hundred fifty or three hundred milligrams as your dose when using canakinumab and Stills?

Yeah, I have a handful of patients who were on long standing high dose of steroids. I'm talking about honestly more than forty milligrams at times, have to admit. I'm not sure why it took so long to get on board with the biologic sometimes honestly. But I had a handful of patients who had long standing robust inflammatory phenotype, unable to wean down from forty milligrams or so with severe steroid induced side effects that I did use three hundred to begin with on these handful of patients. Usually I don't, but when there's a pressing urgent need to find something that really works fast and adequately to be able to allow weaning of steroids, that's the situations that I picked up.

Olga?

Yeah, I agree with Apostolus. In patients who present with more severe disease or the ones who failed multiple treatment options before they went on canikinumab, I would probably start with the three hundred milligram dose. And when they achieve remission, I would taper down to 150. Although in some of my patients who have milder phenotype or they didn't fail other treatments before, I tend to start with one hundred fifty and only go to two hundred if it's not sufficient in milder cases.

I've even gone up to four fifty for some really refractory patients but whatever goes up goes down so once they achieve remission I'm very eager to dial it down and I was also mentioning that after I just, you know, presented because that's possible, know, it's a possibility that we can get patients off that and we can do that by decreasing the dose and or increasing the interval and maybe you know I had there were patients there that went with a maintenance every three months until they were off so it's a highly individualized regimen for patients.

All right our next abstract is FRI Friday 05/2005 Tocilizumab discontinuation after remission in Still's disease by Tamai, Kineko and Taguchi in Japan. Olga, you saw this. What do you think?

Yes. So I think it's a great study. And it actually is retrospective review of patients who were treated with tucilizumab between 2012, 2019, and were able to achieve remission. And out of forty two patients who were able to achieve remission with eight milligram per kilogram tocilizumab dose in IV infusions, thirteen patients actually discontinued treatment and they were studied and analyzed by this group. So out of thirteen patients who discontinued tocilizumab because of the remission, not because of other causes, course, six patients were able to stay in remission, is forty six percent of the patients, and seven of the patients relapsed.

And when they looked into reasons why patients relapsed or what was the most common associated factors that led to relapse, they found that duration of thecilizumab therapy had nothing to do with the frequency of relapse, while the intervals between infusions were important. So patients who relapsed had intervals between infusions of three point six weeks, while patients who were remaining in remission had longer intervals of 6.7 patients, which probably reflects a better response to treatment. Also, dose of steroids was important. So patients who were able to wean off prednisone completely or stayed in very low doses were more likely to stay in remission. So in remission group, they had zero milligram of prednisone, while in the relapse group, patients were on five milligram of prednisone.

And also they noticed that patients who were older while they were treated with tocilizumab or who were older when they were diagnosed with adults with sickle disease were more likely to relapse. I find this like a very interesting study. And it seems like even in a small percentage of patients, remission of medication is still possible. But there are factors to consider before we decide to taper off treatments in those more complicated patients.

So this was observational. It's instructive, but nonetheless observational. I want to go around the horn and ask everyone what's your rule for allowing patients to go off therapy? Obviously, when you start someone on a biologic steroids and whatever you need to control systemic features of Still's disease. The question the patient is going to ask is how long am I going be on this?

And I tell my patients, I don't know, eight months to eight years and we're going to wait and see. But I'll tell you my rules, but let's start with apostolos. Tell me your rules as quickly as you can. We'll go around the horns so we can give the audience a feel for what they should think of.

Yes. So in my practice, think it depends on the phenotype of the patient, systemic versus chronic articular. It may be less likely to wean and taper faster if a patient is a chronic articular patient versus a systemic one. What I usually do is I space out the interval assuming that they're in remission and monitor very, very closely from every two weeks, for example, to every four weeks. And subsequently, depending on how if they're still in remission, I decide to wean them off.

But I definitely keep them for a good year. No steroids on board. In the background of a DMARC, potentially methotrexate, of course, and then I decide to wean off as soon as their remission.

Petros, what do you do?

Well, I tell the patient that, you know, there's going to be no promises. I think the earlier we diagnose, the more likely we are to bring the patient remission possibly without medication. My rule of thumb is once they're on remission without steroids for six months then we're talking about tapering the treatment potentially to off and I've been able to do that.

Hoglund?

Yeah. I agree with the steroid free interval. It's important that they're able to maintain remission without steroids on board. And then after we start tapering their biologic, I first tend to decrease the dose. Let's say if they were on tocilizumab eight, we can go down to four milligram per kg, or if they were kinikitamab three hundred, we go down to one hundred fifty.

And then only if they maintain remission at that lower dose, I start spacing intervals until we gradually lean off. But I I usually tell my patients at least a year or maybe even more.

So that's what I tell patients. First off, what we're getting is consistency both from the paper and all from all of you is no steroids. And then you change your interval. And if you are successful there, then you might be green lighted. But I do it also what Olga does is I tell the patient, you show me a year of no activity of remission, and then we will be able to go off the therapy.

And then the best you can promise is what they saw in this patient. In this study, that maybe it's fiftyfifty, right? Because there are these people that are going to linger for a long time. I thought this was interesting. I think we need a biomarker, but short of that, does anybody else have another tool?

I don't think there's a lab test that you can monitor. I'll give you my one pearl in monitoring Still's disease. The neutrophil to lymphocyte ratio is kind of cool, but you got to do the math on that. That's kind of interesting. Most people measure ferritin.

It's actually not that good because it's only really super high in fifty percent of people in my opinion. But the one that works really, really well is aldolase. People who have very high aldolase levels, they'll get better when they're improved, but they may not totally get to normal. Aldolase is a good biomarker and it's cheap compared to a lot of other things that are out there. Let's go on to the third abstract from Saturday SAT0557 from Bindoli.

This is how to assess residual disease activity in Still's disease using FDG PET. Petros?

Yes, it goes back to what you were saying Jack that we don't really have a good serologic biomarker and we're looking for anything else in clinical biomarker, radiographic biomarker. There's a few publications the last few years about the use of PETCT or FET MRI and there are a few areas that light up with active Still's disease usually the spleen, the lymph nodes, the bone marrow and the pharynx and by checking an opacity or PET MRI you can possibly pick up residual activity while you know other less perfect biomarkers are not very helpful. So in this study by Carlos Frizzo from the University of Padova, they actually did a qualitative and a semi quantitative analysis of a PET MRI and they saw that the activity correlates actually with the clinical symptoms and can show residual activity while we think that the patient may be in remission. So that may be helpful in what we're saying earlier helping us time potentially the withdrawal of drugs.

Really interesting. I guess the real issue on everyone's mind is how do you get it paid for? Has that been a problem for you? I mean you had some experience doing this. What's been your experience in trying to get this done?

It's not easy with insurances but I've been able to get a less PET CT for some patients and take some persistence and explaining and you know a lot of time on the phone explaining to the insurance company why you want to do it. But I've been successful in getting in a few patients. It was helpful.

These have proven in many studies to be very helpful in FUO patients and systemic disease patients, you know, GCA. CT scans are good at damage, but FDG pets are actually good at these activities. So it's not surprising that this could be helpful in maybe deciding can you wean off therapy or not. Anybody else have experience with this in their center?

In my experience, if you justify it as an FUO workup, it is perhaps a bit more likely for that to be approved. But I think that's very, very random individualized based on the center and so on and so forth. But there could be value absolutely in these patients for

sure. Also, they have lymphadenopathy, then you can explain that you're doing the workup, ruling out maybe haematology malignancy. I think that also helps get me approved sometimes.

All right, let's do two quickies if we can. I'll give you one quickie. This is THU or Thursday April, The application of systems biology in silico tools to optimize treatment strategy in Still's disease. This is a very aggressive big data analysis of basically all data out there. The researchers there use a number of different analytical tools to develop these artificial neural networks, sampling methods and artificial intelligence to find all available clinical information on both the biology of Still's disease and also the response to treatment, looking at IL-one inhibitors, Anakinra and Canakinumab, IL-six inhibitors, Cirilimab and Tocilizumab and DMARR therapy, methotrexate and prednisone.

And I'll just say that it was a very aggressive, very confusing analysis that in the end said it looks like it makes more sense to use an IL-one based approach to treat acute disease targeting the innate immune response and that IL-six could be later on and for more autoimmune features of disease. But it had many failings, including a lot of gaps in information not displayed. But I put it up because it's maybe the future. There are a lot of reports here at this meeting about machine learning and big data and helping to make some tough decisions on your next best therapy in many diseases, not just in auto inflammatory, but also in RA and lupus and other autoimmune diseases. So I thought that was interesting only if that is going to be the future.

Petros, why don't you talk about this? I don't know who's going to do this, Petros or Olga, the 10 registries initial treatment of systemic JIA data from a big large collaborator effort, OP-one hundred ninety seven.

Well, can say a couple of things about it but you know I want the other contributors to jump in. I think it was interesting to see that there is a shift in the therapeutic paradigm where you know after patients fail mCIDs instead of going into methotrexate or other traditional DMARDs in Still's disease they actually go to a more targeted approach with either IL-one or IL-six inhibitors and I think that was obviously more obvious in pediatric systemic GIA or pediatric Still's disease but I think it's catching up with the adult, you know, patients as well and maybe indicates a shift in the way we think about this disease. Otherwise we hear what other people think about it.

Yeah, many countries, eleven forty nine patients followed patients for five to eight years over a time frame of what was it 2012 to 2018. And yeah, this whole frame shift away from DMARR therapy more towards biologic, more towards IL-one seems to make sense, think is the right move. Let's go ask everyone, Olga, what's your preferred first line therapy? Someone's diagnosed, they're in the hospital or they just got out of the hospital, referred to you, they're on steroids. What's your first drug you use?

So usually I start with the nil-one inhibitor and then depends on their coverage, whichever I can get approved for them. I feel like the benefit and side effect ratio is really good. The side effect profile is fairly safe. And from my experience, it's very possible to achieve remission with IL-one if patient responds well to treatment. So this is my go to group of medications.

Typically, inpatient anakinra is the one that's first available because it's on formulary in most of the hospitals, from what I know. And we usually start with that. And we try to switch to longer acting agents later on if patient is not satisfied with the effect of anakinra. And I actually find it interesting that in this particular article, you mentioned that steroid use remains heavy in the first year of treatment. Like seventy two percent or seventy two percent of patients were on steroids in the first year of treatment.

And only after one year, it drops. I feel like in my practice, we try to lower steroid dose and wean off steroids rather faster. So I would say in real life, in my practice, I go aggressively with biologic therapy to minimize steroid use in my patients.

So I think that everyone on this panel is pretty much an aisle one first fan. Nod your heads if that's true. If that's true, then I want to ask a Bustlos and Petros, under what circumstances would you use an IL-six inhibitor first? Anybody who wants to start with that?

Think I've seen some patients with very extensive, aggressive synovitis and arthritis where I feel there's, you know, more, you know, combination of innate immunity but also adaptive immunity. There was a paper by Peter Nygrovitz about that, usually happens a lot more in the chronic vestibular phase and I find that hitting aggressively with IL-six inhibition in a really high dose and short intervals, mean I've gone to every two weeks or every ten days, I think I post what I shared with the patient can be beneficial to that. But I'm always worried about, you know, obviously side effect profile, you know, lot of patients with Still's disease have high LFTs and that, you know, that's part of the disease state, but of course giving a medication that can also potentially increase the LFTs, you know, can be a little confounding. But I found it to be, you know, viable, but it doesn't work in lower doses, it has to be a high dose and often we use in a short interval. And these two cytokines are really the pivotal ones in my opinion.

Yeah, I echo Petrus's comments for sure. In my experience, there have been a few patients on IL-six, though in the heavily articular patients, all normal ferritin. By the way, the IL-six blockade acts normal said with CRPs and they still had some chronic synovitis there. I think it does require a very careful clinical exam on these patients who are to actually be prescribed dial six long term to make sure you're not missing any indolent synovitis, which can lead to distracting arthritis and so on and so forth.

Okay, so I'd like to end our panel discussion with another auto inflammatory condition. And that is Behcet's syndrome, the release study from Hatemi and colleagues, that's abstract OP 28 was presented at this particular study at this meeting here in UR. It's a phase three, double blind randomized controlled trial with a twelve week primary endpoint, two zero seven patients who were enrolled. They had to have greater than three oral ulcers at randomization and greater than two at screening. And they were then randomized to receive either placebo bid or a premilast BID with a twelve week endpoint.

The primary endpoint was area under the curve for the number of oral ulcers. And like other studies that we've seen before, the outcomes here were impressive where the amount of improvement was large in a number of patients that the number of patients who had greater than fifty percent improvement in their oral ulcer pain by week twelve was sixty seven percent, two thirds on aprimolast and thirty six percent on placebo. As you can imagine, pretty much no side effects, some GI, some diarrhea with the apremilast, but otherwise very well controlled. Apostolos, what do you think of this data?

I think it does establish a primalast as one of the for of oral ulcers in relation to Behcet's disease. Clearly, there's a robust improvement. What's striking is answer the time that it takes for that to for patients, I guess, to see relief and improvement. It's as we can see there, the first week or two, then it plateaus, occurs plateaus. You know, within the first couple of weeks, pretty much, know, patients can get relief actually.

They these patients, most of them, it seems that they have been also tried other non biologic DMARDs. I presume perhaps colchicine azathiabrine they don't mention here in the study, it seems like, but I suppose these were the ones that they tried. So I think this is definitely one of the drugs of choice. And I think it's for Bechess oral ulcers at this point.

So rather than talk about our anecdotal experiences using this, it is FDA, well, actually not again, it's now FDA approved and can be used. Does anybody think that Primalas, one, why does it work here? And two, would it work in other auto inflammatory diseases?

That's a good point. I do think that based on its mechanism of action, it does affect innate immune pathways. I guess by the way it acts, it has the capacity to improve symptoms related to innate immune pathology for sure. Mucosal or skin perhaps is tissue target. And wherever there is a condition of innate immune pathology that affects, that implicates these pathways, these may be the drug of choice.

I was recently speaking to Dan Kassner from the National Region of Health and he believes Previlast is an IL-twelve inhibitor, not the most robust but you know downstream from PD-four inhibition inhibits IL-twelve and that's a very important cytokine in the chest disease and also the inflammatory diseases so maybe what we're seeing is the result of this inhibition and there was another abstract from Barcelona in this meeting where they looked at patients enrolled in this study and they looked at non oral or non genital ulcer manifestations and they saw that the tremulos may have a beneficial effect with ileitis, GI disease and the skin that you know the other skin manifestation of Bersets, which could be pseudofolliculitis, for example. So I think there's more to that and I think we're eager to find out exactly how much does it help those very effective patients.

My own belief, looking at the biology of this and being a PD-four inhibitor is that I think most of it's mediated through neutrophil effects. Certainly that might be active in systemic JIA and stills, but maybe we'll see that someday. We'll give the last word on this topic of aprimolast and Behcet's and beyond to Olga. What do you think?

Well, I think that it may potentially work in other conditions, as Pat just mentioned, through mechanisms affecting IL-twelve. But going back to that other abstract, talking about non oral ulcer manifestations, the effect was really limited to skin and GI manifestations. So I'm a bit skeptical about efficacy on systemic manifestations like fevers, lymphadenopathy, and other symptoms that we see in other inflammatory conditions. So I would be very cautious to say it may work in conditions.

Right. I'm glad you put that proviso in because we do not want to encourage that. I would like to encourage the research, but certainly not that therapeutic choice at this point. I want to thank the panel for a great discussion on some really interesting papers here at EULAR. A virtual meeting.

This is a virtual panel. I think we all did great.

So you're in the Paris next Paris is the next one. It is.

Right. We will be there even if the virtual people aren't. Alright. Good night.

Definitely. Great seeing you all.