RheumNow Podcast – Function Follows Form (10.2.20) Save

It's 10/02/2020. This is the RheumNow podcast. Hi. I'm doctor Jack Cush, executive editor of rheumnow.com. It's again the week in review.

This time, it's about function following form, or is it form following function? I think it's function following form because that maxim is really about things you do now that has a downstream effect. Like, can you predict the weather? Can you predict remission? Or can you avert the consequences of smoking?

Or what happens when it's all too late? And how do you define when it's all too late? Very cryptic beginning, don't you think? Let's start out with three regulatory approvals that happened this week. The regulators were busy.

I thought they were at home, hiding from COVID. The FDA announced this week that, galimumab, Symphony Aria was approved for use in children with polyarticular JIA. They also had an extension of the indication for pediatric psoriatic arthritis. They define kids as those little tykes over the age of two with either of those diagnoses. Again, the approval of, a biologic or one of the novel new drugs that we use in a pediatric population is sort of a requirement, that the FDA has put upon the companies to do trials in, uncommon conditions like JIA.

And one of the main things they must do is show, sort of clinical, and pharmacokinetic, pharmacodynamic equivalence. A lot of the trials that allow for the approval do have a clinical component, but actually the PKPD studies are vitally important to showing the right dosing and the safety of the drug. So, SYMPONI ARIA looks good for use in kids with polyarticular JIA and pediatric psoriatic arthritis. Same can be said for, the FDA this week approving Xeljanz or atofacitinib in kids with polyarticular JIA, that was based on a phase three trial, two twenty five patients, an open label run-in, typical JIA design, those who are doing good stay on the drug, and then there's a randomized withdrawal of the drug. And of course, those that stayed on the Xeljanz did very well.

Good, good news, they actually, again, with these new pediatric approvals, the dosing is often weight based, and you need to be cognizant of that. The other big approval, maybe somewhat of a surprise, is filgotinib being approved by the European Commission for use in rheumatoid arthritis. It also got approved in Japan, I believe. And, and again, this is a bit of a surprise because we, a few weeks ago, said that while filgotinib was poised for FDA approval, in the eleventh hour they got a complete response letter saying, hey, we need more data on your sperm studies before we can approve it. Those sperm studies are in progress.

They're not gonna be ready until 2021 or, you know, midway through the year or more. But the EMA went ahead and approved the drug without such data being on hand, I guess they're thinking that not that big a deal and they'll wait for the trials, they could always take it off the market if they needed to. But it is gonna it is gonna be approved and the surprising thing here is it was approved at both doses, a hundred milligram and two hundred milligram. That has not happened previously in The United States for the JAK inhibitors. Outside The United States, other doses, two doses for JAK inhibitors have been approved.

For instance, baricitinib has been approved at four and two milligrams in a number of different countries. So anyway, that's good news for, Gilead, Galapagos, and, those who are looking forward to filgotinib being on the market in the European countries. An update from the Global Rheumatology Alliance, you know, that's the registry that you rheumatologists have worked so hard at enrolling your patients worldwide. The latest update from the website, the GRA shows that there's twenty one, 21, patients that have been enrolled, forty percent of them are RA patients, seventeen percent lupus, about nine percent PSAs, two thirds are on biologics, one third, I'm sorry, two thirds are on DMARTs, one third are on biologics, about thirty percent on steroids or thirty percent on hydroxychloroquine, only five percent on JAK inhibitors, and the good news still is that a lower number of deaths and a lower number of hospitalizations, seven point six percent of patients entered online, had died, and thirty nine percent were hospitalized. There's a skewing here.

That's this, this is the worst possible version of what could happen in our patients, because actually the data across the board, cross sectional data looks even better than this. Eighty one percent of these patients had resolved infections. Again, we look forward to more data from the Global Rheumatology Alliance. So, another interesting study came from a Swiss quality database. This is a study of six sixty six patients with either axial spondyloarthritis or rheumatoid arthritis or psoriatic arthritis, and they assess them as in two month intervals beginning in, I think January, and two months before COVID, two months during COVID, two months after COVID.

I didn't know that we got to after COVID yet, but nonetheless, they said that, early on, consults dropped by fifty two percent, that they had a gigantic increase in remote visits, I assume that's mostly virtual of one hundred and twenty nine percent. They showed that non compliance was slightly increased, during COVID, that when you looked at the axial spondyloarthritis patients during COVID versus before, there was twenty percent non compliance during COVID, and only thirteen percent prior to COVID, and that was significant, suggesting that maybe without guidance, patients were stopping their medicines out of fear. But despite this maybe worrisome trend, there was no increase in flare rates, before, during, or after, and disease activity remains stable. So again, encouraging data when it comes to our patients and the consequences of the corona pandemic. So how does one predict the weather?

Well, you might as well predict remission in lupus, don't you think? And a meta analysis of seventeen thousand lupus patients looked at, you know, and it gives a little divining remission in different ways. Hence, they showed that somewhere between forty two and eighty eight percent of patients will achieve remission in one year. Kind of a big spread, don't you think? But it obviously depends on how they're defining remission and the patients they're taking in.

The same spread was seen with twenty one to seventy percent having remission, out at five years. And so this is somewhat limiting, but I think it's somewhat encouraging. Most of my lupus patients in fact are in remission. The question is, can you predict remission or who won't get remission? Remission was more likely in older patients, those with lower disease activity, surprise surprise, and no major organ involvement.

Well, you'd almost didn't even have to do the analysis to go out with these guidelines, but it still is good to note if your patient doesn't have major organ involvement, is doing well with low low disease, low disease activity, older, congratulations, they got a good shot. However, patients who had positive serologies were negatively associated with remission, too vague a statement. Positive serologies, shouldn't you have positive serologies if you've got lupus? And again, this doesn't make any sense. I think maybe they wanted to say that, you know, serologies that may indicate disease activity like double stranded DNA titers might correlate with non remission, but they didn't really come out and say that.

You know, what you can use to define remission and how patients are to do is complement. Well, Michelle Petrie and her colleague Durkin, did a nice analysis of complement associations amongst their two thousand four hundred, SLE patients. Fifty five percent had a low C3, forty seven percent had a low C4. Amongst those, very few actually had persistently low, like three and four percent. That's really not my experience.

I got a bunch of patients who have persistently low C3s and C4s that really never changed despite how the patient's doing. But that was their results. Low C4 they found was a fairly weak, correlate to clinical disease and or serologic disease, suggesting that maybe you want to hang your hat on the C3 levels. Low C3, noted, was linked to renal disease, serologic activity, and they showed that both C3 and C4 being low was more often linked with anti cardiolipin antibodies, strokes, and deep venous thrombosis, basically VTEs and thrombotic events. So that's kind of, I think, something new in as to how you consider complements in managing your patients with lupus.

A nice analysis by Petrie and colleagues. A meta analysis has looked at, the association of smoking with psoriasis. Ever smoking at any time was associated with almost a doubling of the risk of developing psoriasis in the general population, an odds ratio of one point eight four. Now, is where it gets confusing. If you had psoriatic arthritis amongst psoriasis patients, smoking was associated with a thirty percent lower risk of psoriatic arthritis.

So psoriasis patients and now you're looking at the risk of developing psoriatic arthritis amongst smokers, it was in fact less, but not significantly so. Very confusing, the authors of this paper say that latter point can't be overstated, it's often a methodologic difference. Think about it, smoking gets you psoriasis, you know, smoking doesn't, and then once you're on the psoriasis track, you're set up, one third of you, to get psoriatic arthritis and further smoking doesn't change that risk. So, again, don't over interpret those results as at least as how it looked in the tweet that we put out. A nice study on almost 15,000, RA patients looked at adherence to quality standards of care, things like starting DMARDs, when you start DMARDs, what order you start DMARDs, use of steroids, sequence of follow-up care, etc.

And they basically showed something that you would suspect. We know that early treatment has better outcomes, maybe less erosions, but they're looking at an even greater, endpoint. And the endpoint here is what I call a hard endpoint, hospitalizations. You know, the things that you really should look at, things that are really worrisome, are hospitalizations, death in surgery. Those are the things that I think are more worrisome.

In this particular study, they showed that the patients who had adherence to the quality standards had actually a lower risk of future hospitalization, a fifteen percent lower risk of future hospitalizations. This was most impacted by the early initiation of disease modifying anti rheumatic drugs, least impacted, in fact worsened by the use of steroids. Important take home, showing you that your early aggressive treatment of RA pays off downstream. A study of the DeSear cohort, that's a spondoarth early spondyloarthritis cohort, showed that baseline MRIs of the SI joint could predict future five year later damage. So when they showed that if you had bone marrow edema of the MRSI joint, or even the LS spine, that is also showed later damage at the SI joint and LS spine, and that was significant, like a fourfold and tenfold increased risk for worsening of spondylitis.

We put up something that I think that most people know, but it's a nice study from JAMA. This is a low, there's a low risk of developing TB if you are on secukinumab. As you know that patients go on biologics, not all biologics, but most biologics need to have TB testing prior to getting the drug. But not all biologics have a strong TB risk. We know that it's really strong for patients going on TNF inhibitors, and there's a biologic plausibility for that.

You need TNF to make granulomas and to maintain them. You don't necessarily need IL-seventeen. So even though it's required in the clinical trials and then it's in the package insert, they looked at their experience in the drug development trials of secukinumab and those on placebo, twelve hundred and twelve thousand three hundred nineteen patients, they found that six percent developed a positive PPD, or TB test on screening. So that means they met the definition for LTBI, latent tuberculosis infection, and would therefore would have had, to go on treatment prior to going on the trial or getting on the drug. Over the next five years, LTB as, LTBI, latent TB as an adverse event was reported in thirteen patients for a zero point one percent risk.

That's a one in one thousand risk. Of these thirteen patients, half of them had a prior LTBI result, and seven were newly diagnosed. And when they're newly diagnosed, you have to wonder whether in fact they may have active TB, so you have to culture, you know, sputum and urine and whatever you can culture to look for, active TB. There were no cases of active TB that were reported in the clinical trial experience. This says what I've been saying for a while, you know, for a lot of the other MOAs, the non TNF other MOA biologics, there is a concern about TB, but it is a log order or more magnitude less than that seen with the TNF inhibitor.

So, when chased with, when when challenged with what should I do in patients who I can't use a TNF inhibitor, can use pretty much all the other MOAs, IL-six, you know, rituximab, a JAK inhibitor even, and even secukinumab in the right patient with the right indication. So, again, there is a lesser risk, again, you still have to do TB screening. One of the early reports we put up this week was gabapentin failing in chronic pelvic pain. Not that we're treating chronic pelvic pain, you know, it is a big problem, to twenty four percent of women in The United worldwide in fact, have chronic pelvic pain, but there aren't many treatment options. We use gabapentin for everything, but you do know gabapentin is really only indicated for like, seizures, and, certain forms of neuropathy.

It is really not indicated for the vast majority of uses for which it is used. And so, it's often been written, about the misuse, and, overuse of gabapentin, in treating, especially patients with pain and fibromyalgia, where there actually are a lot of side effects. In this particular UK study, they enrolled, I think it was three zero six women, treated for sixteen weeks with either up to two thousand seven hundred milligrams of gabapentin a day or placebo, showing no difference in the outcomes when it came to their worst pain score or change in their pain scores. Again, this is questioning my use of gabapentin going forward, and that I might want to find other alternatives. Gabapentin is often on the list of drugs that are most likely to cause side effects, and that along with being overused makes it somewhat dangerous.

Lastly, you know, there are a lot of people who've worked on the topic of, difficult RA. And, and, you know, Maya Book had a nice set of articles on this, last year, and UR has, I think, followed her lead and the lead of others in coming up with a task force to define difficult RA. And so they did so. This was a task force that put together, you know, again, multi dimensional equal representation by all the stakeholders. They define this as their the idea of this task force is to come up with treatment guidelines for a trip for difficult RA, but their first step was in defining difficult RA.

So they put that out as a new, report in Alzheimer's Rheumatic Disease that just appeared. And here's the definition. Number one, following EULAR treatment guidelines for rheumatoid arthritis, difficult RA is someone who fails two or more biologic or targeted synthetic drugs after failing a conventional synthetic DMART. Number two, the presence of one of the following, moderate disease activity or more, findings of active disease, inability to taper steroids, rapid radiographic progression, and reduced quality of life due to rheumatoid arthritis. And lastly, defining RA means that there's problematic problems with disease management, treatment management, as perceived by the physician, the rheumatologist, and or the patient.

This is all important, I think because this is something we all deal with when I ask you, know, do you wanna hear about my version of difficult RA? Everyone does, but everybody has their own version and often begins with, you know, well, Mrs. Smith, she's my definition of difficult RA, let me tell you about her. And so, again, thankfully, these only make up 10% or less of our overall RA population, that's my guesstimate by the way, but we do need advances in this area and defining it, think is a nice advance. That's it for this week.

On the podcast. Go to our website, check out these citations and more. Again, you can put in your comments and, things that we can discuss here on the meeting by going to something called back talk. We hope to incorporate those into future podcasts in the future. Next week, we're going to start doing QD videos as a lead up to our ACR Virtual twenty twenty coverage.

Look for our QD videos, short cases. Again, you give us two hours, we'll cover the ACR for you. We're gonna have a really interesting expanded coverage of ACR twenty twenty coming up. Thanks for your time. Stay safe.

Wear your mask.