Contemporary approach to managing fibrotic ILD – new data that will change your approach

0:00
All right.

0:00
Well, for all of you here, thank you so much for joining this evening's program, which is titled A Contemporary Approach to Managing Fibrotic ILD.

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New data that will Change Your approach with Doctor Chris Ryerson.

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I'm Ciaran Scallan.

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I'm an assistant professor of medicine at McMaster University, staff respirologist at St. Joe's Healthcare in Hamilton and at University Health Network.

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And it's my pleasure to be here to moderate the program this evening and to introduce tonight's speaker, Doctor Chris Ryerson.

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He's a professor of medicine at the University of British Columbia and head of the Division of Respiratory Medicine at Providence Healthcare in Vancouver, Canada.

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He leads the Canadian Registry for Pulmonary Fibrosis, which supports much of his research on the diagnosis, management, and prognostication of pulmonary fibrosis.

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He's also led several national and international clinical practice guidelines and consensus statements on the classification, diagnosis and management of pulmonary fibrosis.

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And we're very lucky to have him to speak to us on this topic tonight.

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In terms of a few housekeeping items this evening, we just asked that everyone could make sure that their microphone is muted so we have uninterrupted sound.

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You're very welcome to have your camera on or off.

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We thought it would be best.

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If you do think of questions along the way, please don't hesitate to type them into the chat box.

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And I'll do my best to sort of aggregate those and bring those to Chris's attention closer to the end of the talk.

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The presentation is being recorded and there will be slides available after the program.

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And we're very grateful to receive financial support for these events from Boehringer Ingelheim and the faculty are receiving honorarium for their participation.

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Finally in the spirit of balance and integrity, there are some disclosure slides, I think coming up shortly with our relevant conflicts of interest.

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And of course, because this evening's program is fair and balanced, faculty has been fully responsible for developing all the content.

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And it's my great pleasure now to pass things over to Doctor Ryerson.

1:56
Great.

1:56
Thanks Ciaran.

1:57
Welcome everybody.

1:59
Thanks for joining us on a nice wintery night.

2:02
So as Ciaran said, I'll talk about approach to management of fibrotic ILD or pulmonary fibrosis.

2:10
And as advertised, a couple of disclosures.

2:13
These are Ciaran’s and then these are mine.

2:18
We will be talking about nintedanib and pirfenidone made by a couple of the companies on the screen here and some mitigation of potential bias and the disclaimers as well, which we can come back to if anybody wants to.

2:34
All right, so some objectives for the talk.

2:37
So in the next 50 minutes or so, the goal is for you, the audience to be able to describe the definition of progressive pulmonary fibrosis or PPF, the evidence for treatment of PPF and the factors that influence the treatment approach of PPF.

2:54
And we'll talk specifically about the roles of prednisone, steroids bearing immunosuppressive medications and anti-fibrotic medications.

3:01
So I'm gonna start pretty broad and then we'll hone in a little bit further as we go.

3:06
So interstitial lung disease or interstitial pneumonia would be synonyms.

3:11
ILD can be thought of as a huge collection of a couple 100 different diseases that cause scarring or inflammation of the pulmonary parenchyma.

3:18
Within that one of the major groups is pulmonary fibrosis, which is still a collection of many different diagnosis.

3:25
And those common diagnosis would include things like idiopathic pulmonary fibrosis, connective tissue disease and HP. Notably, IPF in red is always a fibrotic condition.

3:36
Whereas HP and connective tissue disease can cause fibrotic or non-fibrotic findings on biopsy and and seen on CT as well.

3:46
And that will become relevant later on when we look at these across Canada.

3:50
This is from our Canadian registry for pulmonary fibrosis for care PF.

3:54
We see that connective tissue disease is the most common that we see in in Canada, followed closely by IPF.

4:02
We see a lot of unclassifiable, which might be a little bit of referral bias and using relatively strict criteria.

4:07
And then we see a smattering of other things as well and HP representing just under 10% of what we see.

4:15
The other thing that's a long list of again, literally a couple 100 different things that can cause pulmonary fibrosis, but do so quite rarely.

4:23
So we'll talk a lot about IPF, connective tissue disease and HP and unclassifiable ILD in this talk and we'll kind of lump in some of the other causes of pulmonary fibrosis under these, but we'll talk mostly about those four big ones.

4:39
I'm going to take a step to talk about pattern versus diagnosis.

4:44
And this is something that I think as a field we've not done great at over the last decade or well five decades probably.

4:52
So pattern is what the radiologist or the pathologist tells the clinician they see when they look at an image, whether it be a CT scan or a biopsy.

5:01
And then the diagnosis is a multidisciplinary label is what the clinician tells the patients they have. For pattern, we hear things about a UIP pattern or a fibrotic HP pattern, which will probably be renamed in upcoming guidelines.

5:17
We hear about an NSIP pattern and there are others beyond this as well.

5:23
And then from a diagnostic perspective or a multidisciplinary diagnosis perspective, we talk about diagnosis like IPF and HP and idiopathic NSIP.

5:32
And there are a few challenges with this.

5:34
The first challenge is that we aren't doing very many biopsies any longer and we have relatively limited data on radiology pathology correlation.

5:43
We have OK information about IPF specifically, but beyond that we're quite lacking in how well radiology approximates pathology and we're doing very few biopsies now to validate these.

5:58
So the arrows across here where a pattern represents the diagnosis are sometimes not as firm as we would like them to be.

6:08
A second challenge is the specificity.

6:10
So when we see a UIP pattern on imaging or on biopsy, we can see that with IPF, we can see a UIP pattern in HP where you might see some subtle granulomas or it might say UIP pattern in a patient with rheumatoid arthritis where there are some specific features as well that might give you that clue.

6:27
But overall that patient still has a UIP pattern.

6:30
So there's a lot of overlap with multiple different patterns being seen in multiple different diagnosis and multiple diagnosis having multiple different patterns.

6:38
And that's a huge challenge for the field as well.

6:41
And then the third challenge is just how we use these terms.

6:44
And it's important, I think that we keep pattern and diagnosis as distinct items, even though a lot of people will conflate these two concepts.

6:54
And I'll try to keep that clear as we go forward.

6:57
So we come back to the labels that we've used in CARE-PF and the labels that we use in clinical practice.

7:02
These are very much an ideological based approach to ILD classification and terminology.

7:09
And this is largely how we've approached treatment is based on these ideological labels.

7:14
And I think there is increasing data and evolving approaches that suggests that there are alternative classification approaches that might have therapeutic utility.

7:23
And we'll talk a lot about that for the rest of this talk.

7:27
So if we think about very simply, what are we treating most of the diseases that we see and really most of the diseases that that humans encounter are based on having a genetic predisposition, a trigger.

7:39
And then the disease develops.

7:41
And that trigger could be an environmental exposure, smoking cigarettes, having aspiration, having an autoimmune disease that develops.

7:49
And then if you have the genetic predisposition to that, whether that's a Mach 5B gene polymorphism or telomere related disorder, those genetic predispositions lead to the disease manifesting in an individual.

8:05
And then that disease is characterized by a number of different manifestations and we can put together a few different categories of these manifestations.

8:15
That could include features that you might see on CT scan or biopsy, things like ground glass or consolidation or reticulation, honeycombing and so on.

8:24
Those features can be amalgamated into a pattern like usual interstitial pneumonia or nonspecific interstitial pneumonia and so on.

8:33
And those manifestations will present as symptoms and physiologic abnormalities.

8:40
And if we think about our goal here, our goal is to treat the underlying biology.

8:47
And the question is what parts of this flow diagram best reflect the underlying biology in a given patient.

8:54
And there is probably rationale to lots of different answers to that question.

8:59
So if we think about the triggers, we historically have approached things as based on the etiology and the trigger IPF.

9:08
I guess we don't quite know the trigger, although we do know that smoking is a risk factor, potentially repeated aspiration episodes and reflux is a trigger.

9:18
But we would treat the underlying etiology as IPF with an antifibrotic or for non IPF ILDS we would often treat with immunosuppression.

9:27
There's a lot of recent work that's looking at the potential importance of genetics and one that I'll call attention to in a in a little bit is short telomers.

9:36
And there's increasing evidence that we should be considering short telomers in our treatment decisions.

9:43
Features and patterns might offer more treatment insight.

9:46
It's fairly well described that patients with a UIP pattern have more significant progressive fibrosis over time, and therefore you could argue easily that patients with a UIP pattern should be treated more aggressively with antifibrotic medications than those with other patterns.

10:04
There's a lot of overlap to that, however. And then there's a lot of recent work that's focused on Physiology and progressive pulmonary fibrosis, which can be defined with symptoms and CT scan features that worsen over time as well.

10:19
But really it's a physiologic driven definition of progressive pulmonary fibrosis.

10:24
And so this is another part that we can treat as well.

10:29
So what is progressive pulmonary fibrosis or PPF?

10:32
There are a lot of synonyms for this.

10:35
I think now the field is coalescing around PPF as the main term of reference, although PFILD was used a little bit more frequently.

10:42
Historically, other groups have advocated for a progressive fibrotic phenotype or a progressive fibrotic phenotype despite management.

10:49
And some of these get clunkier and clunkier.

10:52
And I think progressive pulmonary fibrosis is the one that's going to be sticking.

10:55
And I'll try to stick to that term.

10:58
So this is a somewhat artificial entity that implies a specific biology that's more likely to benefit from currently available anti fibrotic therapy.

11:06
And this is an entity that really was created by the Pharmaceutical industry when they were trying to figure out what role nintedanib and pirfenidone might have in patients with other types of pulmonary fibrosis.

11:20
When talking about PPF, IPF is typically been excluded from the diagnosis or from that definition.

11:28
And the reason for that really is that we know or at least people think they know that all IPF is progressive.

11:35
And I would argue that that's not necessarily the case.

11:38
But IPF by definition was thought to be progressive and the remaining non IPF fibrotic ILDs may or not be progressive.

11:48
And this entity was created to put a label to those that have progressive pulmonary fibrosis due to something other than IPF.

11:55
And this is a good example of a patient who had progressive worsening fibrosis over the span of a few years and very clearly would meet the definition of progressive pulmonary fibrosis by CT scan, but also would surely have worsening physiology and symptoms as well.

12:08
Different criteria have been used in different clinical trials.

12:14
The INBUILD trial at the top, which I'll present a little bit more data on in a minute to find things based on either having significant decline in FVC greater than a 10% relative worsening over 24 months, or having two out of three other domains that had worsening.

12:30
So milder decline in FVC combined with symptoms or combined with ACT or symptoms and ACT combined together as well.

12:39
So that's the inbuilt criteria.

12:41
There's another study on unclassifiable ILD, which we'll also go over in a minute, and that defined things as an FVC decline of at least 5% or worse symptoms over six months, so a shorter interval.

12:53
There's a RELIEF study that again used an FVC 5% absolute change.

12:57
And then the TRAIL study in rheumatoid arthritis used some other physiologic criteria for progression as well.

13:03
All of these, all of these episodes of progression occurred in what was described as a real world situation in which many patients had been treated with immunomodulatory medication, which is generally considered a standard of care for these non IPF populations.

13:21
So the guideline on PPF has defined PPF as the following.

13:28
It highlighted this for a couple different reasons and maybe we can discuss this towards the end if we have time, what the rationale was for using two domains.

13:37
But the guideline required at least two out of the following three criteria to be met within one year with no alternative explanation.

13:45
And those 3 criteria or domains included worsening symptoms, which was left relatively vague such that clinicians can use their best judgment.

13:54
2nd criterion or domain was physiologic evidence of disease progression, and that was either a decline in FVC or in DLCO.

14:03
And the thresholds listed here as a 5% absolute decline in FVC or 10% in DLCO.

14:10
And then the third domain was evidence of radiologic worsening, which was described in reasonable detail in the guideline as having worsening traction bronchiectasis, worsening ground glass with traction that implies microfibrosis under the resolution of the CT scan, increasing reticulation, increasing coarseness, honeycombing or increasing volume loss.

14:31
The guidelines struggled with this last point in the Gray box a little and decided that current or previous background therapy was not to be included in the definition.

14:42
And you can appreciate that as treatment approaches evolve, it gets more and more complicated to keep track of what is appropriate background therapy.

14:52
So this was purposely not included in the definition such that the definition of progressive pulmonary fibrosis really was agnostic to whatever treatment that that patient had been placed on previously.

15:05
And there's a bunch of studies that have been generated since, since the guideline came out and proposed a set of criteria.

15:12
And I think this is one of the benefits of having a guideline is that it puts a stake in the ground that allows it to then be studied.

15:19
And I'm sure the next version of PPF guideline will have some modifications to these criteria, but it did at least allow us to study these.

15:27
So as I mentioned before, it's commonly quoted that all IPF is progressive, but this really isn't true.

15:32
That's particularly not true if we're using the currently available therapies and if we're applying typical PPF criteria, which people have generally not really applied to IPF or non IPF ILD, the rate of progression is up to 50% over the first year or two of follow up.

15:48
And there are several studies that have looked at this and I'll go over a couple of these that we've been involved in.

15:55
So these two studies both came from CARE-PF the Canadian Registry for Pulmonary Fibrosis.

16:00
Again, one published and led by the Hamilton group and then one led by us.

16:07
And these looked at the rate of progression over time or the rate of meeting PPF criteria over time and different ILD diagnosis.

16:18
And as you can see here, we did include IPF in blue, but we also have HP, CTD-ILD and unclassifiable ILD.

16:26
And over the 1st 24 months of follow up after diagnosis, about half of patients have met criteria for progression based on the INBUILD definition.

16:36
We also included patients who died or were transplanted as also meeting the definition of progression for obvious reasons.

16:44
So about half of all patients with fibrotic ILD met the criteria for PPF within two years of diagnosis.

16:52
Once you meet the criteria for PPF, your outcome is poor.

16:58
And so this is patients who we looked at the survival or transplant free survival after meeting PPF criteria using different definitions of progression.

17:10
So if you met the guideline criteria for PPF, that's a solid black line.

17:16
You can see that about 40% of people have died or been transplanted within five years after meeting those criteria.

17:23
And similar percentages meets the endpoints of transplant free survival, similar percentages meet that criteria for the other definitions of PPF.

17:37
And this is all comparable to IPF.

17:39
So these patients are similar to those who had IPF in terms of their overall outcome.

17:45
An important feature that isn't readily apparent from this figure is that only half of patients met or sorry, at least half of patients met one of the four definitions, but only 17% met all four definitions.

17:58
So there's a lot of, there's a lot of non-overlap in these different definitions of progression.

18:06
And of those who had progression by some of these clinical trial criteria, only half of them met progression by the guideline criteria.

18:14
So the bottom line here is that whatever definition you use for progression, you will be disenfranchising a large segment of the population who had progression by other criteria.

18:24
The point here, I think, is that you need to be very careful about being too strict about applying specific sets of criteria to your patients.

18:34
This is a study out of the US and some UK centers as well that did similar kinds of things, but looked at the frequency of meeting different criteria for progression and the prognostic significance of meeting each of those criteria.

18:50
So they looked at a bunch of different possible criteria for progression.

18:54
So listed down here there is some declines in FVC by different thresholds in DLCO, some worsening on CT scan, worsening Physiology, worsening symptoms, worsening CT and worsening symptoms and worsening PFTs and so on.

19:10
And what you can see, sorry, what you can see here is that the P value for virtually all of these is below 0.05.

19:17
I'm showing that basically all of these criteria and combinations of criteria are prognostically informative.

19:28
When we look at the frequency of meeting each of these criteria, what we can see here is that there is some variability.

19:35
So those with the yellow shade for each criterion or set of criteria, those in yellow were the ones that met that criteria for progression.

19:46
The ones in the dashed red boxes also had an FVC decline of at least 10% relative change.

19:54
So the yellow that's not surrounded by the red dashed line is the extra benefit that would come from using each of these criteria for progression benefit meaning that it would identify more patients with progression.

20:09
And again, the bottom line here is that no criteria is perfect for progression and we should be considering multiple domains.

20:20
So the importance of these criteria as well is, is, potentially different across ILD subtypes.

20:28
Although probably less so than you would expect.

20:31
So this is the same group looking at the same population.

20:35
And if we look at IPF in general on the left, patients with IPF have worse survival compared to other ILD subtypes.

20:44
But if we kind of adjust for those with preceding progression, we don't see much difference any longer and IPF actually ends up being in the middle.

20:54
So preceding progression identifies patients at increased risk of future progression regardless of the clinical diagnosis.

21:03
I think the last one that I'll show about this is the lung function trajectory, the future lung function trajectory and patients who have PPF.

21:11
And again, this is from the same US and UK centers, but different publication.

21:15
And what we see here is again looking at the same criteria for progression.

21:21
We see that once you've met criteria for progression, your FVC decline in the future, it continues to get worse.

21:29
So patients with previous worsening future FVC decline generally occurs.

21:33
However, if you look at the numbers in the two red boxes, there's a lot of variability to this ranging from as little as 8 milliliter change over the next year to as much as 150 milliliter change over the next year.

21:48
So quite a wide range of worsening.

21:53
The interesting part of this figure I think is in the green where if you look at patients who met criteria for progression previously only on the basis of worsening FVC, they're the ones that don't actually progress a whole lot in the next year or so.

22:10
So what this suggests, I think is that there's some regression to the means.

22:13
So if you have an FVC that declines a bunch in one visit to the next, but you did not have worsening symptoms, you did not have worsening CT scan, so it really was just an isolated FVC decline, the next PFT is probably going to look a little bit better than you might expect.

22:30
It's not going to continue on at the same rate if symptoms and CT scans had been stable otherwise.

22:36
And that I think is related to the inherent variability in pulmonary function tests.

22:42
So how I like to define PPF, I like to be a little bit more flexible and nuanced than the guideline is.

22:49
So I like to talk about major worsening of FVC and or CT scan.

22:53
So I'm usually talking about more than a 5 to 8% absolute decline in FVC.

22:59
And there's a bit of an important distinction between an absolute and a relative decline in FVC as written here or I'd like to think about modest progression in multiple domains and that can be PFT's, dyspnea or CT scan.

23:15
I typically don't use cough as a marker of severity or of progression because that can be quite variable.

23:24
All right, So changing gears a little bit to how pulmonary fibrosis is treated.

23:31
So it's important to mention and I won't dwell on this, but there are multiple non pharmacologic or, or I guess some of these are pharmacologic, but there are multiple other components of treatment that we should be talking about.

23:42
And I'll pass these by just because I think these are so accepted that they're probably not really worth discussing too much.

23:50
We just should all be doing these things routinely.

23:55
So how was pulmonary fibrosis treated?

23:57
So prior to 2018, as I mentioned before, IPF was treated with antifibrotics.

24:02
We had good phase three clinical trial evidence to support that and that was good true for both nintedanib and pirfenidone.

24:10
For non IPF ILD we had weaker data, but the data supported in general the use of immunomodulatory or immunosuppressive medications.

24:18
I think the field had coalesced around using mycophenolate for most of this, although there are some situations in which more potent or more rapidly acting immunosuppressant medications would be considered as well.

24:31
The data were weaker for this, and a lot of this was extrapolated from connective tissue disease associated ILD, and especially from Scleroderma.

24:40
There have been a bunch of changes to this approach since then, and there's some reasoning behind this.

24:45
So first of all, things with similar disease behavior might have similar biology, and a lot of what I've shown you so far has been similar disease behavior.

24:55
I think this is somewhat faulty reasoning, but this can be true in some specific situations.

25:00
And the reason that this is probably true in this case is that there's a lot of overlap and a lot of unknown about the biology of different subtypes of pulmonary fibrosis.

25:09
And the existing anti fibrotic treatments, nintedanib and pirfenidone are relatively non selective and so they target parts of the fibrosis pathway that are relatively common across different subtypes of pulmonary fibrosis.

25:23
And because of these three points and especially the latter two that provided the rationale for these clinical trials that I'll cover very briefly now.

25:33
The INBUILD trial from five years ago, six years ago now is probably familiar to almost everybody on the call, if not everyone.

25:40
The study population included 663 patients with non IPF fibrotic ILD, not on background immunosuppression.

25:48
You had to have more than minimal disease on CT scan, mild to moderate disease on PFTs and you had to have disease progression as previously described.

25:58
And the intervention was nintedanib or placebo for a year and the primary endpoint was change in FVC over one year.

26:05
About 2/3 of patients had a UIP like pattern on CT scan.

26:09
This is defined as UIP or probable UIP.

26:13
The demographics as you see here are fairly expected for this kind of study population.

26:18
About 1/4 of patients had HP, a quarter had autoimmune conditions with the mixture listed here.

26:25
20% had idiopathic NSIP, which we can chat about later.

26:29
That's a bit of a pet peeve of mine.

26:31
And about 20% of patients had unclassifiable ILD.

26:36
And as we probably all know, the primary analysis was positive for this study showing that nintedanib was superior to placebo in preventing future FVC decline.

26:46
And the magnitude of benefit was quite similar to what we see in patients with IPF from the previous INPULSIS studies.

26:53
When we look at subgroups, patients who had a UIP like pattern had a little greater magnitude of benefit compared to patients who had other non UIP patterns of fibrosis.

27:06
Importantly though, those patients still did have some benefit, although milder amount of benefit.

27:12
Moving on to the study of unclassifiable ILD, this was an interesting one.

27:18
So this had 253 patients with unclassifiable ILD or a low confidence diagnosis, again, had to have progression and similar criteria otherwise to enrollment.

27:31
And the study of course was looking at pirfenidone or placebo for 24 weeks, so only half a year.

27:37
The primary outcome was change in FVC measured by daily home spirometry over 24 weeks.

27:43
If you're going to design a trial, this is probably not how you're going to do it going forward.

27:47
There were some issues with this trial in terms of the technical reliability and physiologically implausible or impossible results.

27:56
And as an example, one patient had an FVC that improved by 35 liters according to the data generated by the study.

28:04
And that's obviously not true.

28:07
Because of this issue, the authors weren't able to analyze the data using their pre specified analysis plan.

28:13
And so this technically was a negative study simply because they couldn't do the pre specified primary endpoint analysis.

28:22
If you looked however at the site's spirometry, which is how we have done things for every other clinical trial ever done in this area, this was a positive study and quite a positive study.

28:33
Pirfenidone was superior to placebo by almost 100 milliliters even though the study was only 24 weeks in duration.

28:40
So I would consider this a positive study in the secondary endpoints further supported that in general.

28:47
One Interesting bit about this study is that patients who are on background mycophenolate had no apparent benefit, while patients who weren't on mycophenolate did seem to have more benefit.

29:00
The reason for this isn't entirely clear.

29:03
I do wonder whether the patients who are on mycophenolate had more of a non fibrotic picture.

29:08
They still had to have some fibrosis but they probably had a bit more of a non fibrotic picture and the benefit of pirfenidone probably is more and those who have more fibrosis probably weren't as likely to be offered mycophenolate.

29:23
The RELIEF study had different kinds of challenges, but kind of same result in the end.

29:30
So this is a patient population of 127 diagnosis as you see here, similar eligibility criteria.

29:38
This study was done only in Germany and had some recruitment challenges that made them end the study early.

29:45
Despite this, pirfenidone was superior to placebo and preventing FVC decline.

29:50
And this was true with a couple different methods of analysis, although the study wasn't quite as clean as you might like it to be.

29:56
And so there's some, I guess, debates about the overall merits of this clinical trial.

30:04
Again though, I would say that this is a positive study showing that pirfenidone is superior to placebo and preventing FVC decline.

30:13
So this led to guideline recommendations for progressive pulmonary fibrosis and a suggestion for treatment with nintedanib for PPF.

30:22
And you can see here that 29% of the committee voted strongly in favor of nintedanib, 62% voted weekly in favor and 9% abstained.

30:31
The 9% that abstained in this were generally those that felt they were unqualified to comment on, on this, on this evidence, often as one example, because they were pathologists who hadn't treated a patient in 40 years and felt like they should be commenting on this for pirfenidone.

30:52
This was an interesting discussion on that guideline panel and there was a recommendation for further research and to pirfenidone, which I think was an unfortunate recommendation because there isn't going to be further research into the efficacy of pirfenidone, especially with it now being off patent.

31:11
Interestingly, 62% of the panel voted in favor of pirfenidone and 38% abstained.

31:16
And again, a good number of these were people who felt unqualified or people that had some questions about the data from the previous clinical trials that weren't adequately answered in the, in the discussions that were relatively brief discussions from the guideline panel.

31:36
And the reason that this came out as a recommendation for further research is that ATS required greater than 80% of the committee members to provide a vote.

31:44
So even though there was unanimity in the direction of recommendation, we didn't have 80% of people voting and therefore, it was a negative recommendation.

31:53
Moving on to immunosuppression in IPF, I'll just present 1 slide from the IPF NET trial.

32:00
This was looking at prednisone, azathioprine and NAC compared to placebo in patients with IPF.

32:06
And as you see here, there was a lot of bad stuff going on, especially early on when prednisone doses were higher.

32:13
Patients who were treated had greater death hospitalization compared to those who are on placebo.

32:19
So moderate dose immune suppression is harmful in chronic management of IPF.

32:25
There's an interesting story with telomere length that I'm not sure we're quite at the bottom of yet, but there seems to be consistence in multiple different studies, so there probably is a good amount of truth to this.

32:37
This was a retrospective analysis of patients with IPF from the PANTHER, ACE-IPD and another academic cohort.

32:45
The ACE trial was a trial of warfarin from 15 years ago or so.

32:50
And what this study showed is that on the left panels, patients with IPF who had short telomers, the right panels show patients with normal or normal-ish telomer lengths.

33:01
So the panels on the left with short telomers, those who got immunosuppression in blue had worse outcomes than those who got placebo in red.

33:11
And you didn't see that same negative impact of immune suppression in patients who had normal telomere lengths.

33:19
So it seems like there is an interaction between immunosuppression and telomere length where you put those two things together and bad things happen to patients with IPF.

33:30
Interestingly, we see the same kind of thing.

33:32
This isn't quite as clean a picture on this graph, but we see a similar kind of thing with HP.

33:38
So those with short telomeres have worse survival and they also have less potential benefit from immune suppression.

33:45
And I won't go through this.

33:46
This figure is a little bit more complicated to interpret than the one in the previous slide but shows similar kinds of effects of short telomeres and immune suppression and multiple different ILD subtypes.

33:59
So to summarize this again, immunosuppression appears more harmful and less beneficial if you have shorter telomeres.

34:07
All right, so how is pulmonary fibrosis treated?

34:10
So if we come back to that historical dichotomy of IPF gets antifibrotics, non IPF gets immunomodulatory medications, we now have good evidence that if you have a non IPF ILD and you're progressing and specifically if you're having progressive fibrosis, there's reasonable evidence for antifibrotic medications.

34:28
And I would argue for both nintedanib and then for pirfenidone in that situation, even though nintedanib is the only one approved by Health Canada at this point in time.

34:37
If we focus in on this a little bit further, there are some important questions I think about the right side of this diagram.

34:45
So the first question is whether immunomodulatory medications are safe as a default first line treatment.

34:51
And especially in those who have short telomeres, this may not be a safe first choice.

34:56
And this is especially true given that we have pretty limited data supporting these to begin with.

35:04
Related to that, first question is whether antifibrotic medications should be first line in some patients.

35:09
Maybe we should be flipping these two boxes around.

35:12
Thirdly, there might be some patients in which it's appropriate for us to be starting immunomodulatory medications and antifibrotics in the same patients.

35:23
And then lastly, there are going to be some patients who probably don't really need any treatments, but we're not fantastic at picking those patients out quite yet.

35:31
And I'll try to answer some of these four questions in the remainder of this talk.

35:36
So when I think about the contemporary treatment of fibrotic ILD, I think of kind of an evolution beyond what I described as an etiology based approach to management that existed prior to 2018 or so.

35:51
And I think we're moving more and more towards what I would term a morphology based approach to management.

35:56
And this is where we use a variety of clinical, radiological and pathological clues to suggest the likelihood of treatment response to different types of medication.

36:06
And I'll walk through what that looks like in in my eyes at least, I like to think of this in two stages.

36:13
First is the question of whether there is potential for short term therapies to reverse rapidly progressive ILD or to rapidly reverse ILD.

36:23
And then secondly is more long-term treatments that are used to slow future ILD progression.

36:32
I won't go into this in too much detail, but this is getting closer to a treatable traits approach to management, which is taken a lot of other areas by storm over the last few years and I think applies nicely to this approach as well. For short term therapy for rapidly reversible ILD, the things that I think about and trying to decide whether to use these kinds of treatments can be broken down into clinical, radiological and pathological features as listed here.

37:02
So usually we're talking about using moderate to high dose glucocorticoid therapy, which works fast and work well, but we don't necessarily like using them in the long term.

37:12
And the clinical features that suggest the patient might have benefit from this would include acute or subacute worsening over days to weeks.

37:20
Radiological features would include things like significant ground glass or OP on a CT scan and a lot of cellularity or again organizing pneumonia on a biopsy.

37:30
So as a couple examples, predominantly non fibrotic HP where you see a lot of ground glass, diffuse central, modularity with minimal fibrosis, peribronchiolar disease and inflammation on biopsy.

37:43
That patient likely would have a quick and nice response to prednisone as well as removing them from the exposure.

37:50
Patients with myositis associated ILD will often present with an overlap of organizing pneumonia and NSIP as shown on the bottom right, and those patients also will often have the OP components improve quite quickly with Prednisone as well.

38:04
Sometimes we end up giving very high doses of prednisone in that situation because these patients are often admitted to hospital and quite sick.

38:12
And then the long-term therapy to slow future ILD progression is where we come to the immunomodulatory therapy and the anti-fibrotic therapy.

38:20
And again for the immunomodulatory ones, we're often talking about mycophenolates, although that often takes several months to kick in.

38:27
And sometimes we do want to use more rapid onset treatments, things like rituximab or tocilizumab or probably more historically cyclophosphamide.

38:36
But I think more often we end up using mycophenolates and sometimes azathioprine and then for antifibrotic therapy again, nintedanib or pirfenidone.

38:44
That would be the two options there. Versus when we would consider no immediate therapy.

38:52
And generally speaking, these are patients who have very mild disease or who are very frail.

38:58
So as an example, this is a patient who has what we would term more of an interstitial lung abnormality.

39:03
It's not quite clear if they have a disease quite yet and we wouldn't really want to treat this patient until there's been more evidence of progression.

39:13
Typically we wouldn't perform a biopsy in that situation either.

39:17
And then patients who are quite frail.

39:18
So if, if you're over the age of 90, I, I don't think I've treated anybody over the age of 90 and even late 80s.

39:26
I generally I'm not using medications to treat and, and managing more of the extra pulmonary limitations that that patient is experiencing.

39:35
And I think often in that situation, some of these treatments would do more harm than good.

39:41
And then the long-term therapy to slow future progression, the immunomodulatory or the antifibrotic therapy, I think that these are increasingly independent decisions where you should be asking 2 questions.

39:53
Should I use immunomodulatory medication, yes or no?

39:56
And should I use antifibrotic therapy, yes or no?

39:58
And there will be some patients where you want to use both right away and some patients where you will use just one or the other.

40:05
So to start with the immunomodulatory therapy and again mostly this is MMF.

40:09
These are generally patients who have something other than IPF who have the suggestion of significant inflammation.

40:17
And this would be classically patients who have more of an NSIP pattern on CT scan, which this is a classic example of patient with systemic sclerosis and a biopsy right underneath that showing the same kind of NSIP pattern.

40:29
And then a patient who has a typical HP or a bronchiolocentric pattern on CT scan and similar bronchiolocentric inflammation and fibrosis on biopsy.

40:40
BAL cellularity and specifically lymphocytosis would be another clue if you're a BAL proponent and these are patients who you typically would be starting on, on mycophenolate at that diagnosis.

40:56
Patients who you are going to consider more of an antifibrotic therapy approach are those who have features that are more in the direction of UIP or have a lot of fibrosis of a non UIP pattern.

41:10
So classically again a UIP pattern characterized by lower lung peripheral predominant honeycombing with traction, bronchiectasis and reticulation without ancillary features on the left and then on the right, this is again a patient who has a typical HP or bronchiolocentric interstitial pneumonia pattern and there's a lot of fibrosis on this CT scan as well.

41:30
That would suggest that this is probably somebody that you would want to be starting on both antifibrotic and immunomodulatory medication at the same time.

41:39
So I'll, I'll finish with a few take home points and then we'll have some time for questions.

41:45
So take home points, the definition and criteria have been proposed for PPF and recent guidelines.

41:52
I don't think these are perfect, but they are a good starting point and I think they should be considered to be a little flexible when you're applying these to an individual patient.

42:05
There is evidence for both nintedanib and pirfenidone in the management of PPF.

42:09
The guidelines only recommend nintedanib, but I think pirfenidone should be an appropriate option for us to use as well in that situation, particularly as some patients don't tolerate nintedanib and there are some specific populations as well in which nintedanib is potentially associated with a greater risk of side effects.

42:29
Disease morphology or pattern is increasingly used to suggest the underlying biology, response to therapy and prognosis and this is moving us towards a treatable traits approach to ILD management where we might identify traits of fibrosis as an example and want to use an anti-fibrotic.

42:45
Or we might identify traits that are more suggestive of inflammation, in which case we would use an immunomodulatory medication, either prednisone more acutely or mycophenolate in the longer term.

42:55
And I think you can expand that treatable traits approach more comprehensively to talk about an overall management plan for patients with ILD as well, where you're incorporating pulmonary comorbidities, extra pulmonary comorbidities, behaviors and lifestyles as well.

43:10
And then in the long, long term, I think we're hopefully moving more towards a molecular based approach to management where we're using specific molecular markers to identify the biology and not just suggest, but actually confirm the most appropriate targeted therapy for a patient to be using.

43:27
And hopefully the next generation of entered products and immunosuppressive medications will be getting towards that goal.