RheumNow Podcast Favorites Of ACR 2019 (11.22.19) Save

It's the 11/22/2019. This is the ACR two thousand nineteen wrap up video. Hi. I'm doctor Jack Cush, executive editor of rheumnow.com, and this edition is gonna be devoted to ACR nineteen talk. Now it's a week after the ACR.

Are you done yet with the ACR? Are you an update here with ACR? Don't worry. We've got more to give you. We covered so much content in RheumNow during that four day meeting.

We could be talking about this until mid March next year. Don't worry. We won't. This week, next week, and then we'll get back to regular business. I wanna go over with you some of the things I thought that I liked the most at the meeting.

You know, last week, we did a RheumNow Roundup, which is my half of Rheumatology Roundup that I do with Artie Kavanaugh every year. And I think that was kinda interesting. I'll give you, I think, some of those today, but these are the ones that I like from the meeting. I think my first one, you already heard about, but I'm gonna talk about it again. Emipalumab.

Emipalumab, a late breaking abstract presented by Fabrizio DeBenedetti. This is a monoclonal antibody against gamma interferon. It's got a drug name and an and an indication. It's called gamma fat. It's used for, the HLH, primary HLH syndrome, histiophagocytosis, and, it can be used in macrophage activation syndrome.

This could be an earth, shattering, game changing, life saving, new therapy. Right now, with MAS who are usually patients with systemic JIA or adults with systemic JIA or adult Still's, these are the ones who are at greatest risk. Now, can happen in a lot of other conditions, other autoimmune diseases like lupus and scleroderma and lymphoma and bad infections, but, you know, count them all up. It's mostly systemic JIAs who get MAS, and they're not quite as not quite as bad as the perforin driven HLH syndromes, where those people are really sick all the time. But this is a life changing kind of medicine.

It was approved recently, for HLH. It can be used in MAS. It's very expensive. It's like a twice a week infusion. And again, it neutralizes gamma interferon better than what we've previously been using, which was what?

Cyclosporin or etoposide, depending on whether you're a rheumatologist, nephrologist, or etoposide being used by the hematologist. So, they know this works because people have bizarro lab numbers just crash down and get normal. Once they're given these infusions, people who are toxic become relatively stable. Again, in this particular study of nine patients with MAS in systemic JIA, they they showed rapid clinical improvement, dramatic reductions in CXCL nine levels, with the first infusion of this monoclonal antibody against gamma interferon. They were able to lower their steroids.

I think it's a game changer. If you're managing patients with Still's, I think you should know about this, and it's gonna be really effective for people who are sick in the ICU and in the hospital. I also talked about methotrexate last week, but I think it's worth, repeating Dan Solomon's report. 1890 is the abstract number about the CERT cohort. That's the cardiovascular cohort where they tried methotrexate, and no arthritis involved here, just met cardiovascular patients at high risk given methotrexate, and some of the numbers that came out of that are helpful.

You know the toxicity of methotrexate, but do you know the rare toxicity numbers that people get all hung up about? You know, people refuse to take therapy based on one in one thousand risk. What are those risks? Well, let's talk about methotrexate pneumonitis. I saw two when I was a resident, and that was before methotrexate was even approved for use in rheumatoid arthritis, and I really haven't seen a case yet.

A lot of talk about it, but no cases of it. I think folic acid prevents this. But in this study, where everybody got folic acid and usual dose of methotrexate, the event rate was a was higher on methotrexate, but it's really low. Seven cases versus on methotrexate versus one on placebo, and that was a zero point three percent, rate or, actually, the incidence rate was zero point two per one hundred patient years. That would be two per one thousand patients.

This is why we rarely see this. But again, that's the risk. The other rare event is pancytopenia. Now, you know, most patients who get methotrexate, who get cytopenic are gonna get leukopenic before they get pancytopenic. They don't ever get thrombocytopenic without pancytopenia or leukopenia.

They don't ever get a severe anemia without the other elements being involved. The white cells are affected first, and then all the cells get affected. And, of course, it's usually patients taking normal doses going to renal failure and get basically then toxic doses of methotrexate. The risk of pancytopenia here was three per one thousand on placebo and thirteen per one hundred on methotrexate. Not significant, but certainly numerically higher.

Patients need to be on folic acid to also prevent this side effect. Pregnancy and discontinuation. I think this is a big issue, in your patients who have RA and who are on a biologic and you don't know what to do with their biologic. Number one, almost all the biologics can be safely used to get pregnant on. The question is, once you get a positive beta hCG and a positive positive pregnancy test, what what do you do with the biologic?

Do you stop it and whatnot? The general re reflex here has been to stop the biologic and immediately with a positive pregnancy test. My hunch, based on watching some of the data over the last few years, is that that wasn't always as good as continuing the biologic. And that's borne out by two abstracts in this meeting. Abstract twenty two ninety two comes from Italy and Spain, eighty six patients, eighty three patients.

The abstract twenty two seventy nine comes from Germany, seventy patients. They both say exactly the same thing. When they compared patients who stopped at the posit at a positive pregnancy test versus those who continued and may have stopped later or may have continued throughout the pregnancy, there was a threefold higher rate of pregnancy complications, and sorry. First off, a threefold higher rate of flares during the pregnancy. On one of the studies, they actually looked at complication rates, and they showed, again, not only were there more flares, more steroid use, or more preterm births in those individuals who stopped it upon knowing that they were pregnant.

The idea is that you don't know if an RA patient's gonna flare during pregnancy, a third will. A third will be be about the same. A third will get worse. The old idea of eighty percent going into remission once you're pregnant with RA is wrong, wrong, wrong, wrong, wrong, and based on no data. The all the studies I'm talking about with one third, one third, one third are based on metric studies and prospective studies.

So the idea here is get pregnant, and and yes, you could stop, but you run the risk of flare. It may be wise to continue at least into the first trimester, and if patient wants to stop, then you stop. Of course, if this is the first pregnancy and, you know, all first pregnancy moms are all wigged out about drugs and babies being born with three noses and that sort of thing, so they're gonna drive the bus on decision making here, and they're gonna wanna stop therapy, and it's okay to go along with it. However, if they are sick and active with inflammation, no. Continue the drug.

They'll do safe. You can only grow a good baby in in a milieu of no inflammation. So that's something you need to tell your patients. Look for the upcoming ACR guidelines on reproductive health. They're in review with the journal and AR three manuscripts.

It's gonna be really great, great stuff when it comes out. It's a lot of a lot of content. You'll be shocked at how much is gonna be in there. Lupus trials, there was a lot of lupus trials that were presented. You know, negative trials for fendrutinib, the BTK inhibitor, not only in lupus, but also in RA.

I would not be developing a BTK inhibitor. Bad idea. Another c d twenty monoclonal an antibody, obentuzumab, also sort of failed. Didn't look very good. There was a study out of Japan.

I actually had a China teletacept. You know, tasse etacicept has been studied before. Teletacept is a fusion protein, otasi n IgG one. It inhibits both BAF and Apryl. It's supposed to be really good at neutralizing them and decreasing B cell responses.

Well, their results out of China were incredible. So incredible. I don't believe them. We need to see other data. I'm not even gonna go over it.

But the two the two highlight studies were the TULIP studies, TULIP one and TULIP two. TULIP one was presented by doctor Rich Fury, wherein, four hundred fifty seven patients with active lupus, no particular kind of lupus, they excluded really bad nephritis and cerebritis, and and their primary outcome was a SRI four outcome and it failed. Tulip, the drug that they used was anifrolumab, three hundred milligrams or a hundred fifty milligrams, failed against placebo. It did not meet its primary endpoint. There were other endpoints that looked a little better for anifrolimab.

Now anifrolimab, two years ago at EULAR, doctor Furey presented a phase two trial, which was just gangbusters. You know, large delta treatment effects between placebo and the active drug looked like it was gonna be the next savior for lupus. In phase three, it did not look good in Tulip one, especially using the, again, the SRI four standardized main primary endpoint in lupus trials. At the same meeting, a few days later, Moran from Australia presented the results of the TULIP two study, which was kind of the same designs, kind of the same patients, three hundred sixty two patients, anifrolumab 300 versus placebo in in this one year study. Boom.

Now it works. What's the difference? Primary endpoint was the difference. After discovering SRI four was a failed endpoint with this drug, they saw that the patients who were measured by the Bicla response, that's b I c L A, British Isle something or other, response measure were better, significantly better. So they changed the out primary outcome measure.

They went over the FDA. They did not tell the, investigators in the TULIP two study which were blinded. They changed the primary endpoint to a Bicla outcome, and they showed it to be significant. So they changed the game the rules of the game midway. Is that kosher?

Well, it was kosher with the FDA. So what's the count now on anifrolimab and it's where it stands regulatory wise? They got a positive phase two, a negative phase three, and a positive phase three. Do they go in for more, or is this enough to go to the FDA and ask for approval? My guess is they're gonna ask for approval.

Let's wait and see. There are a few abstracts this, this this year on the spondyloarthropics that thought were interesting. Number one, upadacitinib is one of the first to show, efficacy of a JAK inhibitor in patients with ankylosing spondylitis. I think filgotinib did that as well a year ago. Tofacitinib was studied early on in AS did not look so good, although they're back on the drawing board and maybe looking at that.

But this the data was really good. They were looking at, ASAS 40 response rates fifty versus twenty five percent. Pretty impressive data. Also impressive were there were two studies about non radiographic axial SpA. Now you know cerdulizumab has got we talked about that last year.

They got approval based on their trial in non radiographic axial spondyloarthritis. And does that matter? Well, number one, there's not an ICD ICD 10 code for non radiographic axial spots. So do you really need the approval, or do you even see these patients? Again, they they they have MR, they have inflammatory back pain, either MR evidence, elevated CRP, but no radiographic changes to document spondyloarthritis or or sacroiliitis.

So there was a trial, the PREVENT trial with secukinumab using a hundred and fifty milligrams in non radiographic axial SpA positive study, and ixekizumab in non radiographic axial SpA, another year study called the COST x or COST 10 study. They both look good. A lot of non radiographic axial SpA running around there. Where are these patients? I don't see a lot of them.

It's just another indication without an ICD 10 code. Do you see them? Please tell me about this when you see me. So now that I'm on a rant, let's talk about Sjogren's syndrome. Abitacib failed.

Rituximab failed. Pretty much everything failed. Well, this year, tocilizumab failed in primary Sjogren's syndrome. Look at the postings, it wasn't very nice. And then there's another study that, what's it called?

Inalumab. Inalumab is actually a BAF receptor inhibitor, and they had a positive report. They said that they met their primary endpoint with the, ESSDAI, the SDI criteria. That's about 10 variables all lumped together. The unfortunately, the SPRE criteria, which is patient reported outcomes in Sjogren's, was not significant.

Neither was the facet, the fatigue score. And the s s the s ESS dye, the s dye, all the lines are going down together and not much difference if you look at them, but nonetheless, they said it was significant. I'm not blown away. The bottom line is it's all over. By the time you have Sjogren's syndrome, real Sjogren's syndrome, there's no inflammation to be treated here.

I don't know why rheumatologists have this fascination with this. Give them spit, give them some eye drops, you know, manage the rare, rare, rare, rare complications of RTA, lung disease, brain disease, etcetera. Sjogren's syndrome is a burnt out inflammatory post inflammatory state. Then there was a lot lastly, there's a lot of discussion about VTEs and JAK inhibitors. A meta analysis of a number of different, JAK inhibitors showed a slight increase in VTEs, venous thromboembolic events, with all the JAK inhibitors.

As you know, the story on here is the first JAK inhibitor, tofacitinib, wasn't even in the label. No mentions of it in their clinical trial results. The other one, Jakafi or ruxolitinib, not even in the label. No mention of it other than a few cases of portal vein thrombosis post marketing. So then comes baricitinib, Olumiant, from Lilly, and that becomes a big issue.

They have an FDA hearing. It gets part of their label. They had more events with the higher dose, four milligrams. So they get the two milligram indication and a black box, and they're off to the races selling their drug and really with very low event rates. And by the way, they knew about this.

It was no big surprise. It was in their label in other countries. So, we're now looking at all the other new JAK inhibitors filgotinib, upadacitinib, a few others in development worrying about will they have a risk of VTEs, DVTs, pulmonary emboli. Well, again, things change when, Pfizer has a clinical trial study a clinical study looking at long term safety of tofacitinib against adalimumab, high risk individuals. And after analyzing, you know, fairly large study, I wanna say 5,000 patients, some real large number, they showed that not the adalimumab patients, but the tofacitinib patients, especially ten milligrams BID, the dose we don't use in rheumatology only in ulcerative colitis, they had a higher rate of cardiovascular death and also VTEs.

So the big discussion was not what's going on at the FDA because nothing's really changed at the FDA or in package labels. But in the EMA, the European equivalent to the FDA, they are sending out all kinds of warnings. PRAC has now advised the CHMP who's now put a a recommendation forward to the EMA about more stringent rules, basically saying that patients should not go on this drug, tofacitinib, but really all JAK inhibitors are in at stake here, but specifically should not go on tofacitinib if they're at risk. That includes the elderly. That includes fat people.

That includes people who are smokers and on, you know, of of estrogen contraceptives. Obviously, if you had a prior history of VTEs, of any kind, you should not go on the drug. Previously, when they an analysis of the of the Pfizer data, back in May, they made a warning saying, really, nobody should be on the ten milligram BID dose. And if you're an ulcerative colitis patient and you need that, well, you have to weigh the benefits versus the risk. Now they're saying, really, nobody should be on that dose.

Again, benefit versus risk, but there's a bigger warning for patients going on JAK inhibitors in tofacitinib, and maybe down the line other JAK inhibitors. Again, I wouldn't get too crazy about this. The event rates here are really low. The event rate in rheumatoid arthritis is point five, point three per one hundred patient years. If it's augmented by a JAK inhibitor, it goes up to point six or point seven.

So you're talking about one or two per one thousand cases, and everybody's getting all wigged out about it. Yes. Patients going on JAK inhibitors, should counsel them about the side effects. You should look and see if they are at risk for VTEs. If they had a VTE in the past, maybe you should look for alternative forms of therapy.

But if your patients are on these drugs, whether it's, you know, tofacitinib, baricitinib, upadacitinib, and they're doing well and you discover, oops, they had a VTE in the past, I wouldn't change my therapy. I discuss it with the patient and say, we'll monitor you. If you get a clot in your leg or shortness of breath, let me know, I'll know what to do. Anyway, those are the big issues coming out of the ACR meeting. Tune in to the website for more good news from ACR two thousand nineteen next week.

By the way, it's open season. RheumNow live registration is now active. We'll be talking more and more about RheumNow live. It's gonna be, again, the same Friday, Saturday, Sunday meeting beginning 03/13/2020. It's gonna be held in beautiful downtown Fort Worth, Texas.

A grand experience was had by all who attended. We'll see you in Fort Worth. That's it for this week. Take care.