Hey, everybody.

Welcome back to Palm Peeps.

Thanks for tuning in today.

Pumped to be back with another rapid fire journal club.

We're here with two Palm Peeps experts at this point.

We have Robert Warren joining us.

He's a fellow at Johns Hopkins, currently doing his pulmonary critical care fellowship.

And, actually, about to start some research into vaping in young adults.

You'll have to let us know what you find.

And Luke Hedrick, who is our rapid fire journal club editor.

He's a Palm Beach pro.

Luke, it's good to see you.

How are you doing?

Hey, David.

It's good to see you too.

I'm good.

Good.

Robert, how are you?

I'm good.

I'm good.

Alright, guys.

Well, what are we talking about today?

Which which article, what condition, Luca, take us away?

Yeah.

So today, we have a pretty interesting article that Robert brought to us.

It was published in the New England Journal in May.

It's first line treatment of pulmonary sarcoidosis with prednisone or methotrexate or the PREDMETH trial.

Robert, do you wanna tell us a little bit about kinda what made you wanna talk about this?

Yeah.

I I brought this trial not just because it's in the New England Journal and was presented at ATS, but, because it's it's not a huge industry sponsored behemoth.

Right?

Sarcoidosis is a rare, heterogeneous disease that has very few randomized controlled trials to support therapeutic options.

And so this trial gives a wealth of data, but it also presents unique challenges for interpretation.

Yeah.

I love it.

I was so excited to actually see, like, another RCT published in this space.

I feel like there's just such a a dearth of information, unfortunately.

So, alright, let's get right into it.

Is there any kind of relevant background do you think we should know or keep in mind when we start looking at the results here?

Yeah.

Absolutely.

This was a trial of prednisone versus methotrexate.

It's called the PRINT meth trial.

And, so to describe a little bit about those two drugs, right, prednisone is the first line treatment for sarcoidosis.

We know that it works.

It causes short term improvement in pulmonary function, decreased symptoms, decreased radiologic abnormalities, but comes with the whole array of steroid side effects that we know and love or

hate: weight gain, sleep problems, hypertension, diabetes, the whole nine yards.

In spite of that, it hasn't been tested head to head against any steroid sparing agent, And the sarcoidosis guidelines note that there's no existing controlled evaluation of glucocorticoid treatment efficacy in preventing pulmonary function decline in severe pulmonary disease.

Methotrexate, on the other hand, it is the most commonly used steroid sparing agent, but the evidence for its use is pretty limited.

There's one twenty four patient trial from the year 2000.

It showed a modest reduction in glucocorticoid dose.

So overall, the guidelines gave a conditional recommendation based on very low quality evidence, and recommendations for other kinds of immunosuppression are based on current practice.

So there's a real gap here, and we need to understand when and how to use steroid sparing agents in sarcoidosis.

Yeah.

I I I love it.

I feel like the beginning of POM Crit Fellowship was learning to love steroids and how quickly they made people feel better.

And then the rest of POM Crit Fellowship has been learning to hate steroids and, you know, all the terrible things they do to people after they make them feel better initially.

One thing too, I guess, that I've always been taught about methotrexate that it's nice to see some data in this paper around is that it has a slower onset of action.

So, you know, you talked about how quickly, prednisone makes people feel better.

And I feel like at least before the trial came out, I don't know that I've been reaching for methotrexate for first line therapy just be out of this concern that it may take too long to start working and people just kinda need to get better faster.

And so I think it's a really interesting question to ask about whether that's actually true or not.

Yeah.

And I'll just add one you know, I love this trial as well.

I think providing guidance in a really common condition that we all learn how to manage, but that we all probably learn how to manage mostly on expert opinion.

I just think in general, methotrexate is a drug that we as pulmonologists probably have not been using enough or been as comfortable with.

And there's always reports of it with methotrexate lung toxicity, which, you know, in general, multiple literature studies have shown you can use it without having too much issue with that.

And so any trial that's sort of saying, Hey, we should have our minds wrapped around this as an option, I think is helpful for us in the potent credit community, because we should really know how to use this drug.

Yeah, absolutely.

So maybe without any further ado, Robert, do you wanna tell us a little bit about what they did, what the study design was?

Yeah.

So CREDMETH was an open label, randomized, noninferiority trial that was conducted at 17 hospitals in The Netherlands.

They included pulmonary sarcoid patients writ large and that this is tough to define because it's a heterogeneous disease.

But they specified that the patients had to have radiographic parenchymal abnormality, so not just lymphadenopathy, but also some marker of impaired lung function.

So that could have been, forced vital capacity less than 90% or predicted, a DLCO less than 70%, or a decrease in either of those in the preceding twelve months.

And this is sort of to go in line with it it should be somebody who needs treatment for sarcoidosis, not somebody who is mild enough that they are going to go without treatment.

They also excluded patients who are not treatment naive, who had received immunosuppression before, or patients who had the primary indication for treatment being extrapulmonary, such as neurosarcoidosis.

The the only thing I'd add here, and and, Dave, to your point about how if you ask 10 pulmonologists how to manage sarcoid, you'll get, like, 11 answers.

I don't know if if you guys' practice is different or if your experience with this is different, but I feel like the idea of an indication to treat for pulmonary sarcoid is also, in and of itself, like, kind of murky.

You know, the obvious ones are obvious, but there's a lot of people that I've run into in fellowship who feel like feel pretty differently about some of the more moderate, moderately mildly symptomatic patients and whether steroids are really beneficial or not just because, you know, so many of these folks do get better without treatment over time.

And so I think here, it's just worth kinda calling out that the indication for treatment was this quote unquote moderate or severe symptoms and then a risk of worsened health or death, which kinda when you look in a little more detail is mostly just extensive ILD or pulmonary hypertension, which feels a little more reasonable to me and a little less wishy washy.

Yeah.

I I think it's a really great point.

I I think multiple things that you learn during pulmonary fellowship, and then on as a pulmonary attending are interesting about sarcoid.

And you certainly nailed one of them is that most people don't need treatment, and especially the people who don't have pulmonary involvement, we'll have a ton of these people in your clinic who got a random CAT scan, had lymphadenopathy, got a biopsy, showed sarcoid, but they're otherwise fine.

And you're mostly just watching because this usually is a process that, thankfully, and a lot of people burns out and then doesn't cause any other problems and maybe just left with some chronic sequelae.

But so this is an interesting thing about trials in general is that we're gonna answer this non inferiority question about prednisone or methotrexate, but it also kind of gives you a nice guideline of how you should think about when I wanna treat somebody.

You know, this trial is designed by people who are experts in the field.

We're gonna look at the data, but they're gonna just look at outcomes going forward if you started treatment based on this indication.

It's by no means a trial of these are the best indications to treat.

Right?

Like, we don't have three different options and we see how people do long term.

But I do think it's a nice window for you to have going forward to say, hey.

This was a trial for a patient who are treatment naive of sarcoid, who had some pulmonary involvement based on these metrics.

And when I have a new patient, maybe I can match them up and say, would you have fit in this?

Is you a person who should probably get some upfront immunomodulatory therapy?

Yeah.

I love it.

Thank you, Dave.

So maybe we talked about who they were trying to include and who they were trying to exclude.

Do we wanna just quickly go through, their table one and kinda who was actually in the trial?

And then we can maybe get through their methods and intervention.

So, Robert, who did the Yeah.

Manage to actually enroll?

So based on these inclusion criteria where you had to have some changes in your pulmonary function, the mean FEV one was 70% predicted.

The mean FVC was 77% predicted.

Mean ratio was point seven two.

Mean DLCO was 70% predicted.

So these are kind of moderate to to mild, abnormalities in pulmonary function.

Also, all the patients, again, because this is an included criterion, had pulmonary abnormalities and lymphadenopathy.

For the demographics, importantly, the trial is conducted in The Netherlands, so they only had seven percent black patients, which is unfortunate.

It was also not a particularly overweight group.

Their mean BMI was twenty six point four, and that may may or may not translate to The United States.

Yeah.

I like it.

I think, the only other things I'd call out because it, is the when you talk about their pulmonary or parenchymal abnormalities, there were interestingly lower overall rates of fibrosis in the group.

I think it was around, like, ten to fourteen percent in the two arms.

So it was a lot of, like, the, parenchymal involvement.

I'm assuming a lot of nodular issues, but not a lot of frank fibrosis and scarring.

And so, hopefully, theoretically, at least, like, a a place where an intervention may still have some time to be really effective in undoing some of that damage.

The only other two things I'd mentioned too is that the epidemiology here was not quite what I would have expected, at least for a US cohort.

I know this was not done in The US.

So it was mostly men.

There were around seventy percent plus male patients in the trial and were overwhelmingly white or Caucasian.

And that's kind of the opposite, actually, I feel like, of what we see with sarcoid in The US where it's more common in black and in female patients.

And so, I think helpful, Robert, that you called out some of these things that may or may not align with the patients that the three of us at least are more likely to see here in The US.

So, Robert, can you tell us about what they ended up doing for these patients?

What was the protocol for the two drugs?

And then what kind of endpoints were they looking for?

Yeah.

The protocol was, a prespecified titration for, for both medications and globally, this was a decrease in prednisone over the study period, which was a twenty four week period.

And they, they measured lung function, throughout the study period as well as quality of life measures, and an increase in methotrexate in the other arm.

So they we went over the study period from forty milligrams a day of prednisone down to ten milligrams a day, and they went up from fifteen milligrams a week of methotrexate up to twenty five, milligrams a week.

Forty milligrams is a relatively high starting dose of prednisone in reference to the SARCOI trial, which you previously covered, Lou.

We put twenty milligrams of prednisolone seems non inferior to forty milligrams in that trial, and there's no difference in any outcome.

But regardless, they try to get down to a lower dose of prednisone.

And also anecdotally, I'd be curious to hear what would you think about this.

The trying to get up to twenty five milligrams a week of methotrexate is a lot.

As we'll talk about, not not a whole lot of the patients were actually able to achieve that dose in this trial.

Yeah.

I think it's a a great point.

I have definitely seen it here, but I don't know that I, see it in the kind of standard protocolized way that they were doing it in the trial.

Like, I feel like when I've seen Methotrexate pushed beyond fifteen, because that's typically also, around where we're starting, is, someone who really tolerates it really well and has partial improvement.

But it's not a kinda across the board dose increase that we're doing in a, like, a rigid way here.

Yeah.

I I I think the risk of going blindly towards a high dose like that is that someone has side effects, they don't tolerate it, and then they wanna stop the medication altogether, which is you run a little bit of a less risk in a trial where you're sort of in a well communication and well monitored status, but probably is why in in clinical practice, we really usually get to a lower dose and then sort of assess where we are a bit.

Although, as you guys already talked about, that can be tough with methotrexate, which takes a little while to act.

Right?

Because you might have to be patient and and wait for that to kick in.

Right.

And and I did like that they had established protocol for dealing with some of the side effects, so switching to subcutaneous methotrexate, which is better tolerated, reducing the dosage before actually crossing over.

So what outcomes were they looking for?

The primary endpoint was change in FVC over the study period.

We talked about the limitations of this metric in when we talked about the, impulsive trials for IPF.

FVC is known to correlate with mortality in the setting of interstitial lung disease.

I wasn't able to find anything about, in sarcoidosis specifically, how it matches up, although we have some indication that in the general population, lung function is important over the course of a lifetime.

And, you know, I think the FEC as, or as an outcome is an interesting one and reasonable in this standard for, a couple of reasons.

The first is that, you know, obviously we think physiologically, it makes sense that a metric like this that we're measuring will be correlated with disease severity.

But also if you were trying to look in this population at a more clinically meaningful outcome, you would need huge numbers because, like, this is a pretty healthy population.

So you're not gonna have mortality.

Right?

You're probably not even gonna have hospitalization.

Right?

And so, if you were trying to look for something, you know, clinically impactful like we often do, you would just need enormous numbers given the rate of event would be so low.

So I think choosing a physiologic metric, while it might have its own limitations, makes a lot of sense.

Absolutely.

Especially with a disease like sarcoid that's, like, not all that common in and of itself.

You know?

I feel like there's always this tug of war between what's practically doable and what's, like, the optimal outcome or steady design, and I I kinda feel like, maybe that's what was done here just given the overall rates of sarcoid in a population.

You know?

Hundred percent.

And another important point is that they did get at some of these more patient centered outcomes with the health related quality of life.

So it it's not as if we're only looking at FVC.

Yeah.

Absolutely.

Well, in regards to FVC, this is a non inferiority trial.

So, Robert, can you maybe just walk us through that a little bit, what they chose and what that means?

Sure.

So most trials are superiority trials.

That means that the whole confidence interval has to go on one side of of the null, and implies that one drug is better than the other.

A non inferiority trial is instead asking the question, is this drug not that much worse than another drug trial?

And you pick a non inferiority margin, which is the boundary beyond which one drug is unacceptably worse than.

The trick is that you have to pick this number.

And so, it wasn't entirely clear to me why they picked 5% in this trial.

They they said in their supplement because FEC measurements show biologic variation, and variation less than 5% is not considered clinically relevant.

Five to me, 5% seems pretty small, actually, so that it's a pretty stringent margin.

I'd be curious to see what you all think.

But, that's how they set up the trial.

Yeah.

I think that's that's reasonable enough.

I think somewhere in that, like, five to 10% range decline in in FEC is often what it'd take to be a significant change.

And so, somewhere on the lower bound of that, but I still think, you know, overall, a relatively reasonable cut reasonable cut point here.

So, Robert, we talked a little bit about what they did and who was in the trial.

What did they find?

The top line result of this trial was that methotrexate was noninferior to prednisone for FVC at twenty four weeks.

The between group difference in least squares mean change was minus 1.17 percentage points favoring prednisone.

They also break down the differences between groups by week as there were a lot of questions as to the time to effect of methotrexate as compared with prednisone.

And it seems at the beginning of the trial that prednisone does better in terms of changes in FVC as well as quality of life.

And then throughout the trial, those changes kind of, even out.

In terms of other outcomes, adherence was a challenge in this trial.

We knew that people were going to have difficulty tolerating both of these drugs, and there was a significant number who crossed over in both groups.

So nine out of seventy patients in the prednisone group had methotrexate added to their regimen and eight out of sixty eight switched to prednisone due to an adverse effect.

So this presents a challenge for interpretation of the results, right, because the crossover between groups in a non inferiority trial make the groups look more similar.

It'll make the treatment look non inferior.

Yeah.

I think it's a good point.

I think it's interesting too as this maybe we can segue a little bit into thinking about safety because, you know, so many of our drugs have these tough side effects.

But, yeah, to your point, if there's a lot of crossover, which I think this is definitely a a fair amount of, I think it's not so high that it makes it, like, uninterpretable for me.

But I do think it's it is something to keep in mind that when you have that much crossover, you're effectively not really treating the two groups all that differently.

And so to your point, it can push you towards not being able to show a meaningful difference.

I want to dive into some of the differences we see in the results on timing, right?

So you talked about the overall results, Robert, that the top line, but there were some things that looked like they might be a little bit different in timing of the impact of these.

Can you comment on that?

Yeah.

So in general, the thought that people had before the study that prednisone works faster, I think was born out by these data.

They have four different, versions of quality of life metrics and all four of them favor prednisone at the four week time point.

But then as the trial goes on, you see less and less of that.

Could that be due to crossover?

Maybe.

But in general, the confidence interval start to inter to overlap between prednisone and methotrexate later on in the trial.

That that's also true for the FEC, the primary endpoint.

Corey.

Yeah.

I think one thing that's kinda hard for me about some of the secondary outcomes that you're talking about is that they ran a lot of tests in this trial.

Like, they ran more than 14 of them, and they did not control for multiplicity.

And so I think it can be helpful, in a saying here where it seems like things are all kind of pointing in the same direction that maybe I'm a little less concerned.

But I always have kind of nagging in the back of my mind that, like, you know, if you run enough tests, eventually, you'll find some things that are statistically different.

And it makes me wonder whether some of the outcomes some of the differences in the outcomes early may have just been some statistical noise.

Yeah.

It's a great point.

You always have to sort of think about how much we're looking at.

I think the night the interesting thing here too, going into it, is that mechanistically, some of this might make sense.

Right?

With mprednisone having, as you guys mentioned, that right up front, people feel a lot better.

You know, anecdotally, that especially the, like, just feeling of it maybe wears off for a little bit but then also methotrexate takes some time to kick in and so maybe these two groups get closer together by the end of the end of the treatment period.

Yeah.

I think it's worth talking about too, if we're thinking about, you know, if if our takeaway seems to be that there's ultimately in the long run, maybe not a huge difference between the two medications, but there's some changes in timing.

I think it's worth talking about the side effect profiles of the two drugs because they were pretty different and that could, you know, weigh pretty heavily into your counseling of patients.

So, Robert, I'm wondering if you could kinda help us think through the side effects that folks were experiencing.

Sure.

Side effects were very common in both groups.

Ninety six percent of the prednisone patients and ninety four percent of the methotrexate patients had some adverse effect.

Most of them were mild, so lots of insomnia in the prednisone group.

The methotrexate patients had more headache, cough, rash.

The known side effect profile of methotrexate is established in other diseases.

It causes GI symptoms, LFT abnormalities, moles, nausea, fatigue.

What actually, happened in the trial, though, is that about twenty five percent of the patients treated with mastrexate had liver enzyme elevation, and two patients stopped the drug because of them.

The authors highlight three, serious adverse events related to treatment, two respiratory infections, and one episode of gastroenteritis in the methotrexate group, and just one episode of treatment, immersion of diabetes in the prednisone group.

And so the serious adverse events were low overall.

In the methotrexate group, eight out of the sixty day patients had to switch to prednisone due to an adverse effect that included six GI side effects, two with LFT abnormalities.

And then, five of the sixty eight had progressive disease or cough and had prednisone added on.

Nine out of the seventy patients in the prednisone group had methotrexate added.

Overall, I thought there was a reasonable side effect profile and that, that most of the side effects were able to be managed, but some patients didn't have to cross over.

Yeah.

And I think, this really just underscores how important it was that they spelled out how they were going to deal with side effects up in their protocol.

Just when you see that, you know, ninety five percent of patients give or take, in the trial had some kind of side effect.

I think one thing that was interesting to me too, here is that the side effects from methotrexate seemed more transient.

Like they seemed to go away by week twenty four at a slightly higher rate.

About two thirds of them had resolved at week twenty four with methotrexate, whereas a little under fifty percent had resolved at week twenty four with prednisone.

And I don't know that I have a great explanation for that other than whether, like, weight gain just takes a long time to go away.

And maybe that's what part of what we're seeing.

The, like, prednisone group, on average gained, like, five kilos in weight.

And it could just be that it you know, that's a thing that's gonna linger with people, as I am unfortunately quite familiar with, that weight loss can take some time.

I generally think of prednisone as dose related side effect drug.

Some of it is about cumulative lifetime prednisone dosing, but also the longer you're on it, the more some of those issues start to rear their head too.

Now we all have had people who get it right away and can't sleep at all.

But sometimes if the it's gonna be more of the insidious side effects, like some of the weight gain, skin striations, like change to, adiposity deposits, like, that is like no one notices in the first week or two weeks or three weeks, but then they start to, keep an eye on it later.

I also think methotrexate is one drug that you get at first, and then you kinda maybe feel not great.

And then as you sort of settle into it, it's a pretty well tolerated drug.

So that could help explain it as well.

So I'll kick it to both of you guys.

We've talked about a lot of great stuff.

We talked about the outcomes.

We talked about the adverse effects.

We talked about, some of the some of the crossover between this.

Other major discussion points that you think people should keep in mind when they're interpreting this trial or things that either limitations or just kind of points of interest that you guys noted.

Yeah.

A couple of things that came up for me.

I'll just highlight the the fact that our US population is a little bit different.

Right?

Specifically, the incidence of metabolic syndrome is higher.

The average BMI is higher.

So that that may affect the adverse effect profile of prednisone specifically.

The other thing about this trial is that it was twenty four weeks long, and we really wanna know what are the changes in the long term in somebody's lung function?

What what are the the rates of exacerbations and hospitalization and ultimately more mortality with, sticking to one strategy or another.

The the other, I think, elephant in the room is that a lot of experts are using upfront combined abatrazate and prednisone.

This trial didn't address that directly.

So I'm curious what what your all thoughts are about where do we go from here.

Yeah.

I agree.

I think, ultimately, one of my takeaways here is that both these drugs seem to work, but prednisone maybe works faster with at the cost of maybe some more side effects.

It makes me wonder whether a shorter birth burst of prednisone, maybe at a lower dose, like, you know, where the this trial was designed before, SarQuart was released, which we talked about earlier on the podcast, but that showed no difference in efficacy.

Though admittedly side effects either between forty and twenty milligrams of prednisone.

So I wonder whether maybe a lower dose with a shorter burst of prednisone upfront could capture some of that early improvement benefit and then kind of transitioning quickly into the therapeutic effect of methotrexate.

And maybe that captures the best of both worlds, but I don't know that I have enough data to make an informed statement about it.

So that is something I would love to see in the future here.

Yeah.

You're hitting the nail ahead.

Often on Rapid Fire Journal Club, we are using practice defining trials.

Right?

Like, this is, like, what we do now.

I think this is different.

I think this is an exciting time for Sarcoid in that we are doing there are two sets of trials out there.

There are novel therapeutics that are coming out that are working their way through phases one, two, and coming up to three.

And then there are now these, like, breed trials, Sarcoort, this one, where we're actually looking at the upfront routine management.

These are not new drugs.

We've been doing this for a long time, but trying to hone in on what might be the best protocols.

So I think we can say from this trial that it seems in a pretty well conducted trial that in terms of efficacy reduction, that there's non inferiority between these two drugs and that maybe there's a little bit difference in the timing.

But Robert, your question is very valid.

It's like, does that change what I'm gonna do?

Or am I gonna do a different third option, which is a combination of these two drugs that I think works really well?

We are planning on some episodes here on Paul and Pepys on this, on sarcoid treatment.

And I would divide it into mild or early pranquebel lung disease and sarcoid, and then sort of advanced progressive fibrosis disease associated with sarcoid.

So please stay tuned to those.

And Robert and Luke, you'll both be invited to join for that to continue this discussion.

But I think that your question hones in on this is, this trial you should know as a Poem Fellow.

Does it, is it practice defining?

Does it change or do things?

Probably not yet.

It's just gonna be in informational into some of these expert discussions going forward, I would think.

It also serves as a scaffold for future trials.

As we talked about, there there's no established protocols out there, for define one, for defining who gets treatment is challenging and then for, having established TAPRs.

So now future clinical trials can refine on what they did here.

Yeah.

Absolutely.

I love it.

I think one of my big takeaways here is that we need more research.

Oh, well.

That's it.

Do you guys so we usually end with a bottom line, or I kinda swooped in and gave my bottom line.

Or anything else to add to that for the last takeaway sentence for this from either of you guys?

Yeah.

I think the way that I think about this is that, at least with respect to lung function changes, both methotrexate and prednisone are reasonable upfront initial therapy options, for patients with pulmonary sarcoidosis and parenchymal involvement.

But their side effect profiles and their onset of action probably differ.

And so you can inform some shared decision making around your treatment plan, whether it's, you know, one of these two or that third thing.

I think this is really helpful data to kind of guide your discussion with patients.

All right.

All right.

Well, this is a to be continued rapid fire journal club.

Thank you, Robert.

Thank you, Luke.

I think this is a great discussion.

Let us know what your guys' thoughts are, or if you have any other questions that you have for us, and and we'll address them in some future episodes.