Rheumatoid Arthritis–Associated Interstitial Lung Disease: Risks, Recognition, and Collaborative Management Strategies
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So sorry, I'll just start again.
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So welcome everyone.
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I'd like to welcome you to another great
session in the Masterclass.
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This is on rheumatoid arthritis
associated ILD risk resignation, sorry,
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risk recognition,
recognition and collaborative management
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strategies.
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I'm really thrilled to be admitting
people while we're talking.
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We have a great turn out and I'm happy to
be with two experts.
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So Doctor Caylib Durand,
the rheumatologist, will know well.
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He is an MD and a PhD.
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He is in Calgary,
Alberta and he's part of the Peak Medical
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Specialty Center.
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He has an expertise in Scleroderma,
but also other CTDs and inflammatory
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arthritis and knows a lot about ILD.
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In addition,
I have with me Doctor Ciaran Scallan.
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He is an assistant professor of medicine
at U of T.
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He is an active participant at the
Respirology and Lung transplant group.
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He has a real interest in ILD and he's
part of the UHN Transplant Center Network.
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I'm Doctor Janet Pope.
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I'm a rheumatologist and professor of
medicine who runs a connective tissue
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disease,
various clinics and I have an interest in
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ILD as well.
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And I'm at Western in London, ON,
So everyone welcome.
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So some housekeeping, the Q and A,
I will be monitoring the chat.
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So that's how you can ask your questions.
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And I will be monitoring.
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So we might interrupt the speakers at
appropriate times to answer your
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questions.
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You can have your camera on or off.
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There's enough bandwidth with the
attendees to have it either way.
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Please mute your microphone.
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We do like hearing the dogs bark,
but that's a different program,
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not this one.
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And please don't forget to do the
evaluation.
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We'll go to the next slide as well.
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So this program is solely sponsored by
Boehringer Ingelheim,
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and supporting the speakers and as a
moderator, I hope I'm being paid for this.
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We'll see.
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But anyway, BI has many products in,
well one product and another one to come
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very soon in this area.
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And they gave full license for the
presenters to do and present what they
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thought was appropriate.
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Next slide. For mitigating bias.
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If you sense bias, please let me know.
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Certainly the presenters were able to
prepare their slides and say what they
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thought was important.
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And if something is off label,
such as Nerandomilast,
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which is not on label at all,
now we will tell you that.
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And that's not necessarily what we're
going to talk about today.
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Next slide.
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So these are my disclosures.
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Next slide and these are Caylib's,
next slide and these are Ciaran's.
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So welcome everyone and our presenters
will be bantering back and forth.
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Our objectives are really threefold
identifying the risk factors and
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manifestations and overall disease burden
and RA associated ILD.
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To look at evidence based diagnostic and
therapeutic strategies of which we do
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have many now.
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It's quite exciting and who should follow
what, when and that's the third objective,
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collaborating between the respirologist
and the rheumatologist for our patients
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and really clearly delineating who's
prescribing what and communicating back
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and forth.
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So let's turn it over to our speakers and
I think we're going to have an excellent
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session and welcome everyone for coming.
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Thanks so much, Doctor.
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Thank you, Doctor Pope.
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I really appreciate the very kind
introduction and really, you know,
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happy to speak on this topic tonight and
I appreciate we have sort of two major
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populations in the audience tonight.
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And you know,
I have to say my most fulfilling work
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really is collaborating with our
colleagues in rheumatology.
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So it's it's great to be able to present
in this forum.
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So Doctor Durand and I have the pleasure
of going through rheumatoid arthritis
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associated ILD and I think, you know,
it's key to understand, you know,
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that rheumatoid arthritis is of course,
you know,
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probably what best known for causing a
significant arthritis and problems with
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with joints.
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But of course it has a very significant
amount of extra articular manifestations.
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We'll be focusing on the lungs tonight,
but again,
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sort of a multi system disease important
to recognize as such and can present in
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many, many different ways.
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Rheumatoid can affect the lung as well in
many different ways.
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I think in respirology,
this is one of the diseases that can
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cause problems and really all
compartments of the lung from the big and
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small Airways to the pleura and then
pulmonary nodules and of course the
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interstitium as well,
which is what we'll be focusing on today.
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You know,
interstitial lung disease is a very broad
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term that I think describes very well.
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I think in essence,
the disruption of the normal architecture
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of the pulmonary interstitium.
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This is one of my favorite photos here
from Murray and Nadel.
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It's an Electro micrograph of a healthy
rad interstitium and really shows how
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dynamic this structure is from panel A to
panel D.
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This is the sort of normal movement of
the lungs really through the respiratory
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cycle and shows how important and dynamic
this structure is and and really
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highlights how important it is to
maintain sort of a very delicate but
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important architecture of the lung to
allow it to normally function.
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It's when this normal structure becomes
disrupted by inflammation and ultimately
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fibrosis that leads to the problems we
see with interstitial lung disease.
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And that is restriction of pulmonary
physiology and impaired gas exchanges,
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that alveolar capillary interface becomes
quite thick.
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The pathogenesis of RA-ILD is not fully
understood like many ILDs,
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but we're gaining increasing
understanding and like many problems,
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we understand that this is probably a
very complex interplay of very specific
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risk factors, notably in RA-ILD.
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Smoking is one of the big ones and a
genetic predisposition and we're starting
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to understand some of these specific
genetic problems more and more as time
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goes on.
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What's the scope of the problem?
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Well,
rheumatoid arthritis is probably the most
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common connective tissue disease.
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It's estimated to affect approximately 1%
of sort of all studied populations.
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And what about in the Canadian context?
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The best most recent information I could
find estimates somewhere around 374,
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000 individuals are living with
rheumatoid with around 20,
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000 incident cases per year.
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And importantly,
ILD is the most common extra articular
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manifestation.
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And depending on which case series you
look at,
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there's the recent evidence suggests
somewhere around 10 to 30% of patients
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have clinically significant ILD.
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And importantly,
it is the leading cause of mortality in
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rheumatoid arthritis.
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On the,
the right side of the slide here you can
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see some very nice data from Ontario by
Lee Fidler and some of my colleagues at
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UFT who looked at our Ontario sort of
wide data ranging from the years 2000 to
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2018,
looking at both the prevalence on top and
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the incidence below of, of RA-ILD.
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And you can see that again as as time has
gone on,
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the both the prevalence and incidence of
RA-ILD is increasing and it's
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predominantly concentrated in generally
older individuals,
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somewhere between the ages of 50 and 70.
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But you can see this overall trend of
increasing prevalence and incidence over
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time,
somewhere around 21 per thousand RA
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patients have ILD in Ontario with an
incidence of approximately 3 per thousand
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as well.
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So very, very nice robust data from, from,
you know, at least Ontario,
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which probably is reasonably extrapolated
across other provinces as well.
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So a significant and growing problem.
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So what about screening a diagnosis?
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And I think this is particularly salient
to our colleagues in,
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in rheumatology as to, you know, again,
there's lots and lots of people with RA
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and of course not everyone has ILD.
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What's the best strategy or approach to
screening and detecting interstitial lung
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disease?
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I think there are two sort of, you know,
major sort of guidelines for this from
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both, you know,
ERS and EULAR and then in America sort of
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the CHEST and ACR guidelines that were
published.
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And I think they do agree on most things.
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One thing they definitely agree on is
that there's sort of a very low quality
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of evidence.
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And a lot of these recommendations are
conditional,
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but I think it forms a very nice
framework and structure for how to
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approach patients with RA when thinking
about potential lung manifestations.
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This is an adapted slide,
I think which I think amalgamates sort of
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the general recommendations from both of
these major societies and I think really
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flows well and is a good general
framework for thinking about screening
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for ILD.
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So of course,
first establishing a diagnosis of RA is
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extremely important.
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And then the question becomes,
is there increased risk for ILD?
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And I think there's a fairly robust
evidence base to sort of point out
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particular characteristics of patients
who are at particularly increased risk.
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I've listed these in the box on the right.
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And again, these are not exhaustive,
but I think are the best with the best
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evidence base.
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These factors that should be strongly
considered as those who should be
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screened.
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These are individuals with high titer
either rheumatoid factor or anti CCP,
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those who have a significant history of
cigarette smoking or at an older age at
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the diagnosis of rheumatoid arthritis or
those of the very high disease activity.
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Additionally,
patients with a male sex or higher body
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mass index would be considered at
increased risk for ILD.
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So having a having a sort of review and
and think about whether any of these
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features are present.
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I will also stress that obviously a very
important clinical assessment asking
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patients about respiratory symptoms,
auscultating for the presence of crackles
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and maybe examining for the presence of
clubbing would also be quite valuable.
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But again,
if none of those are present and you just
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have some high risk features,
I think screening would then be indicated.
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And the guidelines I think are fairly,
fairly good in agreement and thinking
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about a combination of PFTs and HRCT or
high resolution computed tomography as
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tools for screening for interstitial lung
disease.
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Now, again,
this is very resource dependent and,
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and I, I appreciate that again, access to,
to it definitely HRCT may not necessarily
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be rapid or easily accessible,
but should be considered as part of the
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out of your screening tool when possible.
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If both of the,
so if your PFTS are normal or pulmonary
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function tests are normal and HRCT is not
suggestive of ILD,
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I think you can go into then sort of a
monitoring protocol as you would for
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these patients in your clinics.
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But again,
be mindful to monitor for signs or
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symptoms of ILD or respiratory symptoms
in general.
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And then there is mentioning the
guidelines to consider annual rescreening
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in patients with those high risk features
that I mentioned before.
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Again, you know, resource utilization is,
is an important consideration.
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PFTs, I understand,
are much more easily accessible and maybe
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a more reasonable consideration for sort
of longitudinal screening,
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but I would have a low threshold to
consider HRCT if there's any significant
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degree of suspicion.
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If ILD is confirmed or diagnosed based on
these associated tests,
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I would strongly advocate,
and I'm very biased,
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A referral to your respirology colleagues
to consider assessment of disease
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severity, understand characteristics,
symptom burden,
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and then come up with a collaborative
approach to management,
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which I think Doctor Durand and I will
speak on a little bit later this evening.
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Great.
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Before before we go because this is
really helpful,
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but we do have a burning question which I
think we can address.
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So the question is what is seronegative
RA?
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More importantly for this lecture is
what's the frequency of ILD in
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seronegative RA and is it different?
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And Caylib,
because you treat RA every day,
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do you want to just try to answer that
because we just heard that a risk factor
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is RF, CCP, one or both positive,
often high titer.
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So are seronegative RA patients at risk?
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So I mean,
so just to answer Carrie's question,
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what is seronegative RA?
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And we like to unfortunately drop
everything into that.
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So it's a catch all diagnosis
unfortunately.
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But in general, I would say yes,
there's still an increased risk.
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There is still legit rheumatoid arthritis
in there.
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But again, you know, that population is,
you know,
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whether it's a lower incidence is
probably a less amount of ILD in there
00:11:53.782 --> 00:11:56.200
because of those higher risk factors.
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They're not usually in that population.
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But it's a good question, Carrie,
because with respect to, you know,
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what is that and is it all RA related?
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And you know,
sometimes over following these patients,
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they turn into psoriatic arthritis,
they turn into other diagnoses.
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So it's a little less clear in that
population.
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And so that's why we do make that
distinction to really identify those high
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risk group risk factors, right?
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And we certainly don't do CarP and Sa and
all these other antibodies and the
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whatever it is 1333ADA,
which who knows what that's actually
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measuring other than it does really help
us to think of erosions and inflammatory
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arthritis.
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So we don't measure every single factor
of an auto antibody that might be
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positive.
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Ciaran, would you agree with that,
that along the way because you're
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sometimes seeing these people from a
transplant perspective fairly end stage
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for every RA patient who might be
considered for transplant,
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can you kind of give us what percent is
probably RF positive versus negative?
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Because I realize you have the dilemma of
is this an older guy who smoked - to his
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IPF?
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Yeah, that's a that's a great question.
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And it,
it's a bit hard to apply the retroscope,
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especially at end stage of disease.
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I could maybe speak better from ILD
clinic.
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It's not uncommon that seronegative RA is
one of the diagnosis that kind of become
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uncovered when ILD tends to be the first
sort of recognized manifestation of
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disease.
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And, and,
and whether that's a selection bias,
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these patients often end up in our
combined clinics and end up being
00:13:30.582 --> 00:13:32.160
diagnosed with seronegative RA.
00:13:32.160 --> 00:13:33.320
So, so a bit of bias there.
00:13:33.320 --> 00:13:39.160
But I wouldn't exclude the possibility of
ILD if you have a seronegative disease.
00:13:39.160 --> 00:13:41.933
And I think if you have any of those
other high risk features,
00:13:41.933 --> 00:13:45.280
I think you should still apply that model
and consider it as a possibility.
00:13:46.160 --> 00:13:47.000
Absolutely.
00:13:47.040 --> 00:13:48.120
So that's great.
00:13:48.480 --> 00:13:49.400
We'll continue.
00:13:50.160 --> 00:13:50.480
Awesome.
00:13:50.480 --> 00:13:50.880
Thank you.
00:13:50.880 --> 00:13:53.200
So I'm gonna talk about HRCT.
00:13:53.480 --> 00:13:56.320
Apologies if there's any radiologists in
the crowd, but I'll do my best.
00:13:56.920 --> 00:14:01.858
HRCT or high resolution computed
tomography is really a critical tool that
00:14:01.858 --> 00:14:04.360
we rely on very heavily in ILD clinic.
00:14:04.360 --> 00:14:06.703
And it's,
it's very important to understand the
00:14:06.703 --> 00:14:10.463
involvement and extent of disease in
patients with suspected RA or confirmed
00:14:10.463 --> 00:14:11.880
RA and pulmonary involvement.
00:14:13.120 --> 00:14:14.610
And,
and the most common radiographic
00:14:14.610 --> 00:14:15.160
presentations.
00:14:15.160 --> 00:14:19.063
And remember we're talking about ILD
tonight is really I think twofold,
00:14:19.063 --> 00:14:21.720
but there are a diverse number of
presentations.
00:14:21.720 --> 00:14:25.750
But for the scope of tonight,
usual interstitial pneumonia or UIP is
00:14:25.750 --> 00:14:29.840
the most common pattern in around 35 to
40% of those being diagnosed.
00:14:29.840 --> 00:14:34.235
And then NSIP or non specific
interstitial pneumonia represents another
00:14:34.235 --> 00:14:34.480
30%.
00:14:34.480 --> 00:14:37.103
And these are sort of classification or,
or,
00:14:37.103 --> 00:14:39.960
or descriptive patterns that are observed
on CT.
00:14:40.000 --> 00:14:41.840
And I've included a couple of examples
here.
00:14:42.160 --> 00:14:45.324
So the top panels A&B are a good representation of the UIP
00:14:45.324 --> 00:14:45.720
pattern.
00:14:46.200 --> 00:14:49.242
And again,
this is a very fibrotic looking scan with
00:14:49.242 --> 00:14:51.080
often basal predominant disease.
00:14:51.080 --> 00:14:53.536
And you can see here there's a lot of
reticulation,
00:14:53.536 --> 00:14:55.661
traction bronchiectasis or
bronchiolectasis,
00:14:55.661 --> 00:14:59.299
and then perhaps some honeycombing as
well where there's those stacked cysts
00:14:59.299 --> 00:15:00.479
along the subplural area.
00:15:01.000 --> 00:15:04.411
There may be some subtle ground glass
usually interspersed around the areas of
00:15:04.411 --> 00:15:04.800
fibrosis.
00:15:04.800 --> 00:15:07.600
But really it's that reticular change
that's predominant finding.
00:15:08.440 --> 00:15:10.740
To contrast that to the findings in panel
C&D below,
00:15:10.740 --> 00:15:13.000
you can appreciate this is a very
different appearance.
00:15:13.000 --> 00:15:15.160
This is really much more ground glass.
00:15:15.160 --> 00:15:17.142
So you could see a really sort of fuzzy
or,
00:15:17.142 --> 00:15:19.621
or sort of very poorly defined opacity
appearance and,
00:15:19.621 --> 00:15:23.181
and here quite common in our connective
tissue disease almost this wedge shape
00:15:23.181 --> 00:15:25.480
sort of spreading out from the center of
the lung.
00:15:25.920 --> 00:15:27.651
Again,
you could see some fibrotic changes as
00:15:27.651 --> 00:15:27.840
well.
00:15:27.840 --> 00:15:29.892
You see some of these Airways are
abnormally dilated,
00:15:29.892 --> 00:15:30.880
particularly in the bases.
00:15:31.120 --> 00:15:33.960
And there is of course some articulation
and other fibrotic findings.
00:15:34.200 --> 00:15:37.233
But if you can appreciate this is a
really much more inflammatory looking
00:15:37.233 --> 00:15:37.520
change.
00:15:37.520 --> 00:15:39.880
And this would be a very good example of
NSIP.
00:15:40.240 --> 00:15:43.123
Again,
both can be seen in our ILD and the HRCT
00:15:43.123 --> 00:15:47.029
pattern is important because it really,
there's been very older,
00:15:47.029 --> 00:15:51.474
but very good data to suggest that really
outcomes and survival are very,
00:15:51.474 --> 00:15:54.478
are often in,
in many conditions dictated by your
00:15:54.478 --> 00:15:55.320
pattern on CT.
00:15:55.720 --> 00:15:59.414
And you can see here that in the lower or
red curve, really the, the survival,
00:15:59.414 --> 00:16:01.845
you know,
this is a Kaplan-Meier curve and survival
00:16:01.845 --> 00:16:03.996
over time,
there's a very early and sustained
00:16:03.996 --> 00:16:07.691
separation between those patients who
have a UIP pattern versus those who have
00:16:07.691 --> 00:16:08.720
an NSIP pattern on CT.
00:16:08.840 --> 00:16:11.960
And this,
this does echo in other diagnoses as well.
00:16:11.960 --> 00:16:14.060
But in RA this,
this has been a sort of very well
00:16:14.060 --> 00:16:15.320
observed and sustained effect.
00:16:15.320 --> 00:16:18.637
So when, when discussing with patients,
you know, levels of concern or,
00:16:18.637 --> 00:16:21.448
or what to expect,
radiographic pattern are certainly one of
00:16:21.448 --> 00:16:24.720
those very important characteristics that
that's necessary to discuss.
00:16:26.640 --> 00:16:28.358
So pulmonary function testing, you know,
when,
00:16:28.358 --> 00:16:30.918
when patients are are being screened or,
or there's a high suspicion,
00:16:30.918 --> 00:16:31.760
they're often referred.
00:16:31.760 --> 00:16:35.131
And just to maybe orient people who are
less familiar with looking at PFTs,
00:16:35.131 --> 00:16:36.240
this is a typical report.
00:16:36.240 --> 00:16:38.813
The formatting will of course vary
depending on the lab,
00:16:38.813 --> 00:16:40.891
but the important characteristics to look
at,
00:16:40.891 --> 00:16:44.097
and you may get a lot of these back in
your inbox, are the spirometry,
00:16:44.097 --> 00:16:46.400
the lung volumes,
and then the diffusing capacity.
00:16:46.400 --> 00:16:47.560
And these are very, very important.
00:16:47.840 --> 00:16:51.891
The flow volume loop here is shown on the
right and in sort of restrictive diseases
00:16:51.891 --> 00:16:54.544
like RA-ILD,
the curve will look have a roughly normal
00:16:54.544 --> 00:16:56.715
shape,
but everything will be shrunk down or
00:16:56.715 --> 00:16:58.885
look very,
very small as as the lung volumes
00:16:58.885 --> 00:16:59.319
decrease.
00:16:59.800 --> 00:17:03.473
And you can see in this situation,
the spirometry shows a low FEV1 and FVC
00:17:03.473 --> 00:17:04.600
with a preserved ratio.
00:17:05.240 --> 00:17:07.200
The total lung capacity of the lung is
low.
00:17:07.480 --> 00:17:11.037
And then I think most important,
you can see here the DLCO or the
00:17:11.037 --> 00:17:13.840
diffusing capacity here is severely
reduced at 31%.
00:17:14.120 --> 00:17:16.120
And this is the most sort of functional
measure of the lung.
00:17:16.120 --> 00:17:18.040
This shows how well gases are moving
across.
00:17:18.320 --> 00:17:22.338
And so this would be a very good example
of some of the severe restrictive disease
00:17:22.338 --> 00:17:23.840
which we can observe in RA-ILD.
00:17:23.840 --> 00:17:26.165
So again,
something you might return for one of
00:17:26.165 --> 00:17:29.120
your patients who's been diagnosed.
FVC is a very important-
00:17:29.120 --> 00:17:30.000
Oh, sorry, go ahead, Janet.
00:17:30.600 --> 00:17:33.320
Oh, sorry,
because you'll reiterate that in a second.
00:17:33.360 --> 00:17:37.688
But what if someone,
because a lot of these are older people,
00:17:37.688 --> 00:17:41.040
they've smoked previously,
men more than women.
00:17:41.040 --> 00:17:44.880
What if someone also has, say,
a high residual volume?
00:17:44.880 --> 00:17:49.372
Do you pay attention to that?
and the ratio being preserved...
00:17:49.372 --> 00:17:53.579
So in other words,
how should a rheumatologist or maybe we
00:17:53.579 --> 00:17:59.069
shouldn't kind of consider is it ILD
restrictive with an obstructive pattern
00:17:59.069 --> 00:17:59.640
as well?
00:17:59.640 --> 00:18:04.325
Because we get more and more of these
mixed patterns and I don't think we know
00:18:04.325 --> 00:18:06.520
how to understand who we send to you.
00:18:07.520 --> 00:18:09.160
Yeah, that's an excellent question.
00:18:09.160 --> 00:18:12.460
And as you say, right,
because smoking is such a significant
00:18:12.460 --> 00:18:15.274
risk factor,
the presence of concurrent obstructive
00:18:15.274 --> 00:18:19.494
lung disease or emphysema can often
confound testing PFTs alone will not give
00:18:19.494 --> 00:18:20.360
you a diagnosis.
00:18:20.760 --> 00:18:23.645
They can create a diff-,
a list of differentials and give an idea
00:18:23.645 --> 00:18:24.520
of disease severity.
00:18:25.200 --> 00:18:28.690
But there is an increasing incidence of a
condition known as combined pulmonary
00:18:28.690 --> 00:18:30.480
fibrosis and emphysema or CPFE for short.
00:18:30.480 --> 00:18:33.368
And that's when patients have sort of
scarring usually on the bottom and
00:18:33.368 --> 00:18:34.200
emphysema on the top.
00:18:34.200 --> 00:18:37.120
And they sort of have these opposite
effects on lung physiologies.
00:18:37.120 --> 00:18:40.399
The emphysema increases lung volume,
fibrosis decreases it,
00:18:40.399 --> 00:18:44.388
the clue to us is respirologists are
often patients will have a close to
00:18:44.388 --> 00:18:46.520
normal FVC, perhaps slightly decreased.
00:18:47.040 --> 00:18:50.229
They may or may not have airflow
obstruction because remember, again,
00:18:50.229 --> 00:18:53.008
these two sort of, you know,
pathologies are having opposite
00:18:53.008 --> 00:18:53.920
physiologic effects.
00:18:54.280 --> 00:18:59.098
But what we'll often see is the DLCO will
be severely reduced out of keeping with
00:18:59.098 --> 00:19:00.920
the, with the reduction of FVC.
00:19:00.920 --> 00:19:04.475
And that's a clue to us that there's some
problem either with the blood vessels
00:19:04.475 --> 00:19:06.120
themselves or the OR the lung tissue.
00:19:06.720 --> 00:19:08.899
And, and again,
we'll be very descriptive in our report
00:19:08.899 --> 00:19:09.600
what we're seeing.
00:19:10.080 --> 00:19:13.879
And that and I think that the presence of
a very low DLCO should be an indicator
00:19:13.879 --> 00:19:15.240
that HRCT would be indicated.
00:19:15.240 --> 00:19:17.198
And very often as reporting
respirologists,
00:19:17.198 --> 00:19:18.800
we will mention that in our reports.
00:19:19.320 --> 00:19:22.165
But I think in an RA patient with that
pattern, I would,
00:19:22.165 --> 00:19:25.960
I would very strongly encourage an HRCT
to make sure we're not missing ILD.
00:19:26.600 --> 00:19:27.280
Wonderful.
00:19:27.520 --> 00:19:29.920
And one other question that's about HRCT.
00:19:29.920 --> 00:19:34.583
So someone has asked because I don't even
know what this means,
00:19:34.583 --> 00:19:39.320
but they've asked about what about BIP
pattern on CT for RA-ILD.
00:19:39.800 --> 00:19:43.041
I mean,
I know about COP formerly known as BOOP,
00:19:43.041 --> 00:19:44.960
but I'm not sure what BIP is.
00:19:45.160 --> 00:19:46.920
So there's a question.
00:19:46.920 --> 00:19:48.200
Can you enlighten us?
00:19:48.640 --> 00:19:49.160
Sure.
00:19:49.600 --> 00:19:52.560
So that's maybe a little bit out of the
scope of tonight.
00:19:52.560 --> 00:19:56.371
There's been some reclassification of the
interstitial pneumonias recent
00:19:56.371 --> 00:20:00.391
publication in the ERS which sort of
talks about sort of this bronchocentric
00:20:00.391 --> 00:20:04.515
interstitial pneumonia absolutely can be
observed with increasing frequency in
00:20:04.515 --> 00:20:08.640
patients with connective tissue disease
that is an observed pattern in RA-ILD.
00:20:08.640 --> 00:20:12.198
The exact frequency I think I can't quote
off the top of my head or or I again
00:20:12.198 --> 00:20:14.360
depends on the population you're talking
about.
00:20:14.880 --> 00:20:17.877
It's an excellent question and and I
think that's probably a whole hour
00:20:17.877 --> 00:20:20.000
discussion in and of itself and we won't
continue.
00:20:20.000 --> 00:20:22.440
But one last mini question to it.
00:20:22.600 --> 00:20:26.680
So larger airways would look like they're
involved as well as the alveoli.
00:20:26.680 --> 00:20:28.680
Is that kind of the thing happening?
00:20:29.200 --> 00:20:30.872
Yeah,
it's more about the pattern or
00:20:30.872 --> 00:20:34.443
distribution of the changes again tend to
be along some of the bronchovascular
00:20:34.443 --> 00:20:34.760
bundle.
00:20:34.760 --> 00:20:39.120
So it's it's a radiographic description
and a distribution of the changes on HRCT.
00:20:39.520 --> 00:20:41.880
So someone's been doing their reading of
recent publications.
00:20:42.040 --> 00:20:44.236
But yeah,
I think we should- that deserves a talk
00:20:44.236 --> 00:20:44.720
of its own.
00:20:45.240 --> 00:20:47.120
OK, we'll keep going, but thank you.
00:20:48.240 --> 00:20:49.360
Thank you for the questions.
00:20:50.240 --> 00:20:52.200
OK,
so we're going to pivot now a little bit.
00:20:52.200 --> 00:20:55.038
So we've talked about sort of the,
the scope of the problem and, and,
00:20:55.038 --> 00:20:57.146
and sort of some,
some very basic information about
00:20:57.146 --> 00:20:58.120
screening and diagnosis.
00:20:58.640 --> 00:21:00.849
And we'd really like to pivot now to
talking about management,
00:21:00.849 --> 00:21:03.760
which I think is really the, the sort of,
I think the meat of the, the issue here.
00:21:04.200 --> 00:21:06.213
So this is a,
a really amazing slide from Kerri
00:21:06.213 --> 00:21:08.520
Johannson published a few years ago now
in The Lancet.
00:21:08.520 --> 00:21:12.032
And I think really helps to sort of set
the set the stage or sort of our
00:21:12.032 --> 00:21:14.920
conceptual framework to the management of
these conditions.
00:21:14.920 --> 00:21:18.686
And I will say that that I think this is
a constantly evolving approach as we
00:21:18.686 --> 00:21:22.645
understand more about these conditions,
learn to better phenotype or endotype our
00:21:22.645 --> 00:21:23.079
patients.
00:21:23.360 --> 00:21:25.272
But I think this serves as a very good
foundation,
00:21:25.272 --> 00:21:26.960
I think springboard for our next
discussion.
00:21:27.600 --> 00:21:30.422
You can see along the top here,
this is IPF for idiopathic pulmonary
00:21:30.422 --> 00:21:32.509
fibrosis,
which is sort of our our sort of kind of
00:21:32.509 --> 00:21:34.800
Sentinel or, or you know,
sort of foundational disease.
00:21:34.800 --> 00:21:38.212
In ILD, which is, you know,
the best understood and what we think of
00:21:38.212 --> 00:21:40.240
as really almost a pure fibrotic disease.
00:21:40.240 --> 00:21:43.600
And they're really the foundation of
management is anti fibrotic therapy.
00:21:43.600 --> 00:21:46.989
And with with exceptions,
we think that there's sort of not a huge
00:21:46.989 --> 00:21:50.683
role for sort of chronic or long term
anti-inflammatory therapy in these
00:21:50.683 --> 00:21:51.240
conditions.
00:21:51.840 --> 00:21:52.920
Then it gets a lot more difficult.
00:21:53.200 --> 00:21:55.360
And I think our RA-ILD is a very good
example of that.
00:21:55.360 --> 00:22:00.235
And we have these non IPF ILDs that are
really sort of this continuum or spectrum
00:22:00.235 --> 00:22:01.960
of inflammation and fibrosis.
00:22:01.960 --> 00:22:04.800
And how these two processes interact is
extremely complex.
00:22:05.360 --> 00:22:07.720
And again, you know,
over time may not be consistent.
00:22:08.160 --> 00:22:11.722
And we have to think about all of these
factors about monitoring diagnosis,
00:22:11.722 --> 00:22:14.581
risk of progression,
And then how we integrate our different
00:22:14.581 --> 00:22:16.925
therapies,
including immunomodulatory therapy and
00:22:16.925 --> 00:22:18.799
then antifibrotic or combined therapies.
00:22:18.960 --> 00:22:22.550
And how we incorporate these treatment
strategies over the spectrum of a
00:22:22.550 --> 00:22:25.451
person's disease,
realizing that this may change over time
00:22:25.451 --> 00:22:27.959
and we need to constantly reevaluate our
approach.
00:22:28.840 --> 00:22:30.720
So again,
a very nice place to start our discussion.
00:22:30.720 --> 00:22:33.597
And I'll,
I'll hand over to Doctor Durand for the
00:22:33.597 --> 00:22:36.935
next section. Right,
now as you're handing over wonderful
00:22:36.935 --> 00:22:41.596
comment saying that that slide really is
quite helpful on understanding that our
00:22:41.596 --> 00:22:46.200
patients might go from inflammatory to
fibrotic or a combination and that as we
00:22:46.200 --> 00:22:48.560
follow these patients, they could evolve.
00:22:48.760 --> 00:22:51.420
And for the Rheumatologists listening,
you know,
00:22:51.420 --> 00:22:55.710
we think of this every day that we have
people with inflammatory arthritis and
00:22:55.710 --> 00:22:58.480
then they get say erosion,
so irreversible damage.
00:22:58.640 --> 00:23:01.360
It's the same idea in the lungs,
which I think is helpful.
00:23:01.560 --> 00:23:02.960
So Caylib, on to you.
00:23:03.600 --> 00:23:06.452
Yes,
so I get The dirty side of the guidelines,
00:23:06.452 --> 00:23:09.720
so to speak that everyone's less kind of
consensus on.
00:23:09.720 --> 00:23:14.040
So the screening is a lot less
contentious.
00:23:14.040 --> 00:23:17.440
So there's really broken into two major
categories here.
00:23:17.440 --> 00:23:19.880
1 is the kind of rapid progressive side.
00:23:20.120 --> 00:23:22.966
And so luckily,
we don't see a huge amount hopefully of
00:23:22.966 --> 00:23:25.000
our RA kind of falling in this category.
00:23:25.000 --> 00:23:27.760
It is more than myositis and Scleroderma
patients.
00:23:27.760 --> 00:23:31.956
But just to give it the context,
it really is combination therapy and it's
00:23:31.956 --> 00:23:35.984
kind of all hands on deck with steroids
and then early referral to lung
00:23:35.984 --> 00:23:36.599
transplant.
00:23:37.480 --> 00:23:40.597
And then of course, there's that,
you know, caveat with the MDA5,
00:23:40.597 --> 00:23:42.440
which we won't kind of discuss further.
00:23:42.720 --> 00:23:44.160
We'll focus mostly on RA.
00:23:45.480 --> 00:23:48.771
So when you break it down into that kind
of second set of categories,
00:23:48.771 --> 00:23:50.840
this is more looking at first line
therapy.
00:23:50.840 --> 00:23:55.958
It gets a little more kind of, I guess,
not so straightforward in the sense that
00:23:55.958 --> 00:23:58.865
again,
these guidelines were driven really to
00:23:58.865 --> 00:24:03.794
treat interstitial lung disease and they
weren't particularly only focused on
00:24:03.794 --> 00:24:05.880
things like rheumatoid arthritis.
00:24:06.280 --> 00:24:08.567
And so when you look at the
recommendations,
00:24:08.567 --> 00:24:12.736
they have the preferred therapies being
mycophenolate, azathioprine or rituximab,
00:24:12.736 --> 00:24:15.940
which I think really kind of surprised a
lot of the, you know,
00:24:15.940 --> 00:24:20.159
practicing rheumatologist because we're
like, wait a minute, what are these drugs?
00:24:20.160 --> 00:24:22.240
We don't usually use these in RA
management.
00:24:22.640 --> 00:24:25.732
And so with the addition of
cyclophosamide and steroids,
00:24:25.732 --> 00:24:27.360
that was what was recommended.
00:24:27.360 --> 00:24:31.866
What's really interesting is that they
kind of came out against-conditionally
00:24:31.866 --> 00:24:33.080
against methotrexate.
00:24:33.280 --> 00:24:35.511
A lot of our typical DMARDs, TNFs,
Abatacept,
00:24:35.511 --> 00:24:38.520
which is kind of interesting given the
data that's out there.
00:24:38.880 --> 00:24:41.929
And then, you know,
JAK inhibitors and Sarilumab and they
00:24:41.929 --> 00:24:44.400
didn't really say much about the other
DMARDs.
00:24:45.160 --> 00:24:49.918
They, you know, for respect to this,
they really emphasize treating medically
00:24:49.918 --> 00:24:52.664
first,
obviously before letting them get bad
00:24:52.664 --> 00:24:54.799
enough to need to go to transplant.
00:24:54.960 --> 00:24:59.188
But I think what the real emphasis was is
that it's really important to get the RA
00:24:59.188 --> 00:25:03.213
disease activity under control and you
probably really need to treat to target
00:25:03.213 --> 00:25:05.200
so that we don't have this progression.
00:25:05.640 --> 00:25:08.237
And then when you look,
there's this kind of if the ILD
00:25:08.237 --> 00:25:10.741
progresses,
what you switch to and it's kind of well,
00:25:10.741 --> 00:25:12.039
you switch to anything else.
00:25:12.280 --> 00:25:14.800
And then then funny enough,
this is where you start to see the
00:25:14.800 --> 00:25:15.360
antifibrotics.
00:25:15.360 --> 00:25:18.991
So it's kind of a little bit out of
keeping of our overall paradigm that we
00:25:18.991 --> 00:25:20.760
were talking about on the last slide.
00:25:22.840 --> 00:25:25.745
And so, you know,
going back to some of the data really
00:25:25.745 --> 00:25:28.029
made me kind of look at things because
one,
00:25:28.029 --> 00:25:30.519
they were not really recommending
methotrexate,
00:25:30.519 --> 00:25:34.619
which is kind of interesting because
there's actually quite a decent amount of
00:25:34.619 --> 00:25:36.279
data out there for methotrexate.
00:25:36.520 --> 00:25:40.730
I think most rheumatologists and most
respirologists that deal with ILD on a
00:25:40.730 --> 00:25:44.941
regular basis don't really feel that
methotrexate is now contributing to the
00:25:44.941 --> 00:25:45.160
ILD.
00:25:45.800 --> 00:25:48.720
And so in Calgary we do use a lot more
methotrexate.
00:25:48.920 --> 00:25:53.061
Interestingly enough,
when they went back and looked at all the
00:25:53.061 --> 00:25:58.433
data that there's actually overall lower
incidence of RA-ILD for patients who have
00:25:58.433 --> 00:26:02.640
ever been exposed to actual methotrexate
for any length of time.
00:26:02.920 --> 00:26:06.002
And that when they are on methotrexate
longer term,
00:26:06.002 --> 00:26:09.440
there's actually a delay if they do get
ILD by 3.6 years.
00:26:09.680 --> 00:26:12.059
So methotrexate alone,
interestingly enough,
00:26:12.059 --> 00:26:14.280
actually has some protective benefit here.
00:26:14.840 --> 00:26:17.640
I can't really say the same about
leflunomide, or hydroxychloroquine.
00:26:17.640 --> 00:26:20.080
So there doesn't seem to be as much of a
protective effect.
00:26:20.080 --> 00:26:23.620
So just keeping that in mind because a
lot of times you get told to stop the
00:26:23.620 --> 00:26:26.563
methotrexate or you know,
there was an underappreciation of the
00:26:26.563 --> 00:26:29.000
methotrexate probably more in the
respirology world.
00:26:29.000 --> 00:26:31.800
We really like it because it helps with
inflammatory arthritis.
00:26:33.120 --> 00:26:33.440
Of course.
00:26:33.440 --> 00:26:35.823
Moving onto immunosuppression, you know,
again,
00:26:35.823 --> 00:26:39.497
a lot of us were kind of scratching our
heads a little bit when they said
00:26:39.497 --> 00:26:42.526
azathioprine and a few of the other
immunosuppressive drugs,
00:26:42.526 --> 00:26:44.960
but there is actually evidence for
azathioprine.
00:26:45.800 --> 00:26:49.105
The only problem for us is it doesn't
work great for inflammatory arthritis,
00:26:49.105 --> 00:26:52.453
which of course from a rheumatology
perspective is what we're trying to treat
00:26:52.453 --> 00:26:52.840
the most.
00:26:53.360 --> 00:26:56.160
And it's a pretty tough drug to tolerate.
00:26:56.360 --> 00:26:57.920
It comes with quite a bit of side effects.
00:26:57.920 --> 00:27:01.682
So when you look overall at the
effectiveness of the immunosuppression,
00:27:01.682 --> 00:27:05.654
there is a very interesting publication
looking at a retrospective study on
00:27:05.654 --> 00:27:08.894
protecting the lungs,
both FVC and DLCO and they all actually
00:27:08.894 --> 00:27:11.977
do a pretty good job of protecting from
MMF, azathioprine,
00:27:11.977 --> 00:27:14.119
cyclophosphamide and including rituximab.
00:27:15.360 --> 00:27:18.672
You would think with number wise
rituximab looks better than others,
00:27:18.672 --> 00:27:21.360
but statistically it actually didn't make
a difference.
00:27:21.600 --> 00:27:27.164
But what happened is azathioprine had a
discontinuation rate of anywhere from 15%
00:27:27.164 --> 00:27:27.640
to 30%.
00:27:27.640 --> 00:27:29.600
So it was a very poorly tolerated drug.
00:27:30.520 --> 00:27:34.338
MMF, interesting enough,
actually has most of the data kind of
00:27:34.338 --> 00:27:36.400
extrapolated from Scleroderma ILD.
00:27:36.880 --> 00:27:41.208
And there's actually not a whole lot of
actual data related specifically to
00:27:41.208 --> 00:27:42.120
RA-ILD with MMF.
00:27:42.400 --> 00:27:45.544
And anyone who knows that rheumatoid
arthritis treated with MMF,
00:27:45.544 --> 00:27:48.785
it really is a terrible drug for
inflammatory arthritis doesn't do
00:27:48.785 --> 00:27:49.560
anything for us.
00:27:49.560 --> 00:27:51.840
So we're always having to combine it with
something else.
00:27:52.200 --> 00:27:56.979
And then cyclophosphamide is, you know,
a reasonable option for interstitial lung
00:27:56.979 --> 00:27:59.951
disease,
but unfortunately it comes with a problem
00:27:59.951 --> 00:28:03.040
of lots of toxicity,
including hemorrhagic cystitis,
00:28:03.040 --> 00:28:07.120
bladder cancer, bone marrow suppression,
infections and malignancies.
00:28:09.160 --> 00:28:12.866
And so when we look at our other DMARDs,
you know, rituximab,
00:28:12.866 --> 00:28:15.974
we often reach for a lot more,
at least in Alberta,
00:28:15.974 --> 00:28:20.039
with respect to interstitial lung disease
and rheumatoid arthritis.
00:28:20.440 --> 00:28:23.480
It is actually better than TNF inhibitors.
00:28:23.480 --> 00:28:28.093
So there's an interesting study that
looks at this in reference to one another
00:28:28.093 --> 00:28:32.356
and that you know we're starting to see
rituximab+MMF with the EVER-ILD,
00:28:32.356 --> 00:28:35.217
keeping in mind that these are SARD-ILD
studies,
00:28:35.217 --> 00:28:39.772
some of these are not direct RA-ILD,
there's a subset of populations in here,
00:28:39.772 --> 00:28:43.160
but there is an overall reduction in all
cause mortality.
00:28:43.320 --> 00:28:46.400
So as we can see here,
when you're looking at rituximab versus
00:28:46.400 --> 00:28:48.746
placebo,
we are seeing an improved benefit when
00:28:48.746 --> 00:28:49.920
we're doing combination.
00:28:50.560 --> 00:28:54.000
I had a better appreciation after going
to the data for abatacept.
00:28:54.000 --> 00:28:57.714
I really had kind of not used a lot of
abatacept and I don't know if you know
00:28:57.714 --> 00:29:01.619
anyone else from the rheumatology or even
respirology community can kind of speak
00:29:01.619 --> 00:29:02.000
to that.
00:29:02.320 --> 00:29:04.936
It's funny enough actually has reasonable
data,
00:29:04.936 --> 00:29:09.080
which is why it's odd that the guidelines
came out recommending against it.
00:29:10.400 --> 00:29:13.314
And I don't know,
maybe it's my clinical experience that,
00:29:13.314 --> 00:29:15.727
you know,
abatacept I don't find works quite as
00:29:15.727 --> 00:29:18.240
good as controlling inflammatory
arthritis in RA.
00:29:18.320 --> 00:29:21.113
So, you know,
really pivoting to some of these other
00:29:21.113 --> 00:29:21.640
therapies.
00:29:23.360 --> 00:29:24.751
I don't know, Janet,
you look like you want to speak up on
00:29:24.751 --> 00:29:25.200
abatacept's behalf.
00:29:25.240 --> 00:29:26.960
I do I do.
00:29:26.960 --> 00:29:30.734
So there's,
there's a comment that is screaming in
00:29:30.734 --> 00:29:31.400
the chat.
00:29:31.400 --> 00:29:35.960
It should have one of those Harry Potter
screaming owl letters.
00:29:36.720 --> 00:29:42.354
A person is basically saying,
I'm really tired of hearing that in
00:29:42.354 --> 00:29:46.965
RA-ILD, someone telling,
meaning I'm sorry to say the
00:29:46.965 --> 00:29:53.197
respirologist telling the rheumatologist
to avoid hydroxychloroquine and
00:29:53.197 --> 00:29:57.040
methotrexate and moving on to biologic
ASAP.
00:29:57.240 --> 00:30:00.320
So I think both of you might be able to
comment on this.
00:30:00.480 --> 00:30:03.680
So in other words,
let's say we had- there's two scenarios.
00:30:03.840 --> 00:30:08.320
We have an RA patient with ILD and
they're uncontrolled synovitis.
00:30:08.560 --> 00:30:13.604
We have an RA patient with ILD who's
worsening and respirology is saying stop
00:30:13.604 --> 00:30:18.520
using your lame drugs that can make it
worse and move on to something else.
00:30:18.720 --> 00:30:22.231
So there's two different ways because if
there's synovitis,
00:30:22.231 --> 00:30:25.040
we we'd like to have one drug treat two
things.
00:30:25.280 --> 00:30:29.809
And Caylib was implying drugs that were
recommended against that in the the
00:30:29.809 --> 00:30:32.431
common,
common - meaning as the prescribing
00:30:32.431 --> 00:30:37.140
rheumatologist - we're going to just
ignore that and prescribe something that
00:30:37.140 --> 00:30:40.120
we think is happy for lungs and happy for
joints.
00:30:40.320 --> 00:30:44.358
So Caylib, then Ciaran,
you want to try to address this?
00:30:44.358 --> 00:30:48.892
I guess you know, yeah,
I and coming to that is because usually
00:30:48.892 --> 00:30:52.292
if you're going to reach for
immunosuppression,
00:30:52.292 --> 00:30:54.560
we need something else on board.
00:30:54.880 --> 00:30:56.943
And so I think being told not to use
those drugs,
00:30:56.943 --> 00:30:59.914
if we're going to be using MMF,
we're going to use it in combination to
00:30:59.914 --> 00:31:01.399
control all of the disease symptoms.
00:31:01.400 --> 00:31:03.483
So I mean the simple thing that or like
you said,
00:31:03.483 --> 00:31:05.400
we're going to reach for drug that does
both.
00:31:06.760 --> 00:31:10.243
And I mean we, I,
I have lots of patients with interstitial
00:31:10.243 --> 00:31:13.379
lung disease,
RA on methotrexate who have been stable
00:31:13.379 --> 00:31:13.960
for years.
00:31:13.960 --> 00:31:16.015
If not,
they're actually doing better because it
00:31:16.015 --> 00:31:18.280
augments their biologic or
immunosuppressive therapy.
00:31:18.280 --> 00:31:22.995
So I don't have any kickback or you know,
opposition from the respirology group
00:31:22.995 --> 00:31:27.475
here and about using methotrexate and
that pneumonitis kind of picture is a
00:31:27.475 --> 00:31:30.894
very rare entity,
less than 1% and it is a very different
00:31:30.894 --> 00:31:32.840
kind of picture overall than ILD.
00:31:32.960 --> 00:31:34.200
So right.
00:31:34.480 --> 00:31:39.040
And Ciaran, I think along those lines, we,
there's two schools of thought.
00:31:39.040 --> 00:31:41.934
Well,
the third school where I'm not going to
00:31:41.934 --> 00:31:45.458
talk about that, you know,
methotrexate is bad for ILD,
00:31:45.458 --> 00:31:49.359
but the two schools of contemporary
thought are methotrexate.
00:31:49.640 --> 00:31:51.520
The patient broke through.
00:31:51.760 --> 00:31:53.600
Why don't you add or switch?
00:31:53.600 --> 00:31:56.888
Because their ILD has either developed or
worsened,
00:31:56.888 --> 00:32:00.746
even though we just heard Caylib say 3
1/2 years on average,
00:32:00.746 --> 00:32:05.680
they're reducing the likelihood of ILD,
but it might eventually breakthrough.
00:32:06.240 --> 00:32:10.902
Or the other school of thought is let the
rheumatologist do what we want with
00:32:10.902 --> 00:32:11.680
methotrexate.
00:32:11.680 --> 00:32:16.355
But because the ILD is worsening,
can we please consider helping with the
00:32:16.355 --> 00:32:21.598
treatment unless if it's mostly fibrotic
and then the rest were all just listening
00:32:21.598 --> 00:32:25.200
and yourself have more experience using
an antifibrotic.
00:32:25.440 --> 00:32:31.088
So where do you stand and where do you
see the colleagues standing on the
00:32:31.088 --> 00:32:33.760
methotrexate quagmire conversation?
00:32:34.960 --> 00:32:37.010
Yeah,
I think it's probably less of a quagmire
00:32:37.010 --> 00:32:37.840
than it used to be.
00:32:37.840 --> 00:32:41.208
But I appreciate this as a, you know,
probably a subject of a lot of discussion
00:32:41.208 --> 00:32:41.840
back and forth.
00:32:42.760 --> 00:32:45.944
And I think we'll circle at the end
really highlights the value of, you know,
00:32:45.944 --> 00:32:49.332
close collaboration to sort of talk about
all of our different priorities in terms
00:32:49.332 --> 00:32:50.720
of managing a multisystem disease.
00:32:51.200 --> 00:32:52.640
But I'm not answering the question.
00:32:52.640 --> 00:32:56.808
So I think I would fully agree with
everything that's been said that I think
00:32:56.808 --> 00:33:00.815
our concern for methotrexate as a
contributor to progressive fibrotic ILD
00:33:00.815 --> 00:33:04.280
is approaching a very low level compared
to what it used to be.
00:33:04.280 --> 00:33:06.608
And, and again,
if patients are stable and doing very
00:33:06.608 --> 00:33:08.549
well,
I think most of us would be very happy
00:33:08.549 --> 00:33:09.800
for it to continue with time.
00:33:10.200 --> 00:33:14.076
But I think the key-ish question is what
happens when the FVC starts to decline
00:33:14.076 --> 00:33:17.080
and the HRCT starts to evolve into
something more concerning.
00:33:18.280 --> 00:33:20.654
I think continuing methotrexate is
reasonable,
00:33:20.654 --> 00:33:24.694
but it may at times limit your options in
terms of either changing or combining
00:33:24.694 --> 00:33:25.200
therapies.
00:33:25.200 --> 00:33:29.426
So I think depending on how the sort of
extra-pulmonary disease is behaving,
00:33:29.426 --> 00:33:33.543
it really requires sort of careful
collaboration to sort of decide on what
00:33:33.543 --> 00:33:35.080
the next best step might be.
00:33:35.080 --> 00:33:38.600
And we fortunately have a lot of tools in
our toolkit to think about that.
00:33:38.880 --> 00:33:41.362
I think MMF may be a less attractive
option now,
00:33:41.362 --> 00:33:44.200
particularly if there is very active
articular disease.
00:33:44.200 --> 00:33:46.480
So again,
perhaps another option may be very useful.
00:33:47.240 --> 00:33:50.939
But again, as as the causative factor,
I don't think methotrexate is a big
00:33:50.939 --> 00:33:53.800
concern and and I think it's in that
progressive patient.
00:33:54.280 --> 00:33:57.791
And I think again phenotyping if this is
a really progressive sort of fibrotic
00:33:57.791 --> 00:33:59.924
appearance on CT,
perhaps earlier initiation of
00:33:59.924 --> 00:34:01.480
antifibrotics should be considered.
00:34:02.040 --> 00:34:05.295
How we factor in nerandomilast as it
comes to become more accessible is an
00:34:05.295 --> 00:34:06.120
important question.
00:34:06.120 --> 00:34:08.067
And I'll finally say that
hydroxychloroquine,
00:34:08.067 --> 00:34:11.412
I think pretty much everybody coming into
our combined clinics gets it walking
00:34:11.412 --> 00:34:14.800
through the door and we have no concern
from a pulmonary perspective with that.
00:34:14.800 --> 00:34:16.040
And if it helps there are symptoms.
00:34:16.040 --> 00:34:16.960
I think that's wonderful.
00:34:17.800 --> 00:34:23.236
So hopefully that's, you know, helpful,
I think it is to both the respirologist
00:34:23.236 --> 00:34:24.800
and the rheumatologist.
00:34:25.000 --> 00:34:29.101
And I think that the other key thing you
said and that this will come up in the
00:34:29.101 --> 00:34:32.280
later objective is the dialogue that you
really need to know.
00:34:32.560 --> 00:34:35.998
Why do you- you know,
I don't want you using this drug and
00:34:35.998 --> 00:34:36.640
here's why.
00:34:36.880 --> 00:34:40.680
And we might give the pushback or the
agreement and then we move on.
00:34:40.680 --> 00:34:41.640
[and] have consensus.
00:34:41.880 --> 00:34:47.181
The patient is best treated by, you know,
two different specialties giving their
00:34:47.181 --> 00:34:48.360
opinions together.
00:34:49.920 --> 00:34:53.448
And just to highlight like the
methotrexate shouldn't delay moving on to
00:34:53.448 --> 00:34:54.560
other therapies, right?
00:34:54.800 --> 00:34:57.680
And so that comment to moving on to
biologics ASAP.
00:34:57.680 --> 00:35:02.490
I mean our goal is disease remission and
so it just shouldn't let methotrexate
00:35:02.490 --> 00:35:03.160
delay that.
00:35:03.680 --> 00:35:07.340
So Caylib,
just one last thing and then we'll
00:35:07.340 --> 00:35:12.989
continue to move on because great
dialogue and people are saying well,
00:35:12.989 --> 00:35:18.320
abatacept is in the Spanish guidelines as
treatment of ILD and RA.
00:35:19.600 --> 00:35:22.816
Some people have said,
you know there's patients with abatacept
00:35:22.816 --> 00:35:26.786
that have improved their Scleroderma,
their RA or some patients unlucky enough
00:35:26.786 --> 00:35:27.440
to have both.
00:35:27.720 --> 00:35:32.361
So I think the bottom line is if you can
control the disease activity,
00:35:32.361 --> 00:35:37.590
you're usually not lung unfriendly and
some drugs are better studied and that's
00:35:37.590 --> 00:35:42.689
why the guidelines kind of diss some
drugs because they're looking at grade A
00:35:42.689 --> 00:35:47.200
level evidence and I think we're looking
at real world data as well.
00:35:47.360 --> 00:35:51.280
And I think both lend a hand to help us
on what to do.
00:35:51.640 --> 00:35:53.040
OK, Caylib, back to you.
00:35:53.800 --> 00:35:56.163
Yeah, and just to comment on that,
like I said,
00:35:56.163 --> 00:36:00.004
I don't- didn't use a lot of abatacept
before I think just from all the other
00:36:00.004 --> 00:36:03.107
therapies out there,
but I have a new found appreciation let's
00:36:03.107 --> 00:36:04.240
just say for abatacept.
00:36:04.240 --> 00:36:07.480
So I'll keep it back in the, you know,
in the pocket for those other patients
00:36:07.480 --> 00:36:08.560
that I need to treat with.
00:36:09.560 --> 00:36:13.543
And then just commenting on tocilizumab
'cause there's been a lot of talk about
00:36:13.543 --> 00:36:16.680
tocilizumab and unfortunately it's really
kind of a mixed bag.
00:36:16.680 --> 00:36:20.407
Some studies, I mean not great evidence,
it is either retrospective or case
00:36:20.407 --> 00:36:20.800
control.
00:36:20.800 --> 00:36:25.134
So it's not great evidence,
but it really is kind of, you know,
00:36:25.134 --> 00:36:28.520
an exciting,
it's kind of no better than the TNF.
00:36:28.840 --> 00:36:33.051
And when you look at the analysis here,
you know, it's pretty much on par,
00:36:33.051 --> 00:36:34.960
but you have other better options.
00:36:35.200 --> 00:36:38.741
What's more exciting, however,
is the kind of new entry of JAK
00:36:38.741 --> 00:36:39.360
inhibitors.
00:36:39.640 --> 00:36:41.421
And you know,
when they made the guidelines,
00:36:41.421 --> 00:36:44.667
they probably didn't have enough of the
real world evidence in writing, you know,
00:36:44.667 --> 00:36:47.320
latest clinical trials,
especially with interstitial lung disease.
00:36:47.760 --> 00:36:51.746
And so there was a very good study
published in the JAMA series in 2023
00:36:51.746 --> 00:36:54.957
comparing tofacitinib,
which has probably been around the
00:36:54.957 --> 00:36:55.400
longest.
00:36:55.400 --> 00:37:00.305
I think probably I think in Canada since
you know data has been collected since
00:37:00.305 --> 00:37:04.352
2012, it's been quite a good,
you know at least 10 years and it's
00:37:04.352 --> 00:37:08.890
actually quite protective, so 0.
31 and it actually outdid a lot of these
00:37:08.890 --> 00:37:09.320
others.
00:37:09.320 --> 00:37:11.200
Again, these can't be directly compared.
00:37:11.200 --> 00:37:13.729
This isn't a head to head clinical trial
by any means,
00:37:13.729 --> 00:37:17.040
but it is the best we kind of have as a
meta analysis in a JAMA series.
00:37:17.040 --> 00:37:21.681
So it was interesting to see that
tofacitinib actually has quite improved
00:37:21.681 --> 00:37:22.560
lung outcomes.
00:37:23.440 --> 00:37:28.656
And so on that note,
there was a very interesting abstract
00:37:28.656 --> 00:37:30.160
presented at ACR.
00:37:30.160 --> 00:37:31.760
So not quite a year old,
but getting there.
00:37:32.320 --> 00:37:33.840
I did not see this published.
00:37:33.840 --> 00:37:35.840
I searched high and low from PubMed.
00:37:35.840 --> 00:37:38.138
I thought maybe they would have had the
publication out yet,
00:37:38.138 --> 00:37:39.080
but it's not quite there.
00:37:39.800 --> 00:37:44.581
It's by Serrano and Combarro who
presented the data looking at JAK
00:37:44.581 --> 00:37:47.080
inhibitors and specifically RA-ILD.
00:37:47.600 --> 00:37:51.680
And so as we talked about,
we are kind of limited with options.
00:37:52.040 --> 00:37:56.160
They wanted to look at the safety and
efficacy of JAK inhibitors in RA-ILD.
00:37:56.520 --> 00:37:59.665
This is a national multicenter Spanish
study,
00:37:59.665 --> 00:38:05.000
and they actually used a different group
combination of JAK inhibitors as JAK
00:38:05.000 --> 00:38:09.240
therapy, including upadacitinib,
filgotinib, and tofacitinib.
00:38:09.920 --> 00:38:14.336
And so not great big numbers,
but then again we're used to rare
00:38:14.336 --> 00:38:16.200
diseases so this isn't bad.
00:38:16.200 --> 00:38:18.800
It's not stellar,
but it is a point in the right direction.
00:38:19.600 --> 00:38:24.057
A good chunk of them were in UPA and then
a mix of TOFA and filgotinib with 11
00:38:24.057 --> 00:38:24.960
month follow up.
00:38:26.280 --> 00:38:30.571
And so these are the baseline
characteristics, fairly matched,
00:38:30.571 --> 00:38:33.160
maybe a bit of a difference in gender.
00:38:34.000 --> 00:38:37.919
And then when you look at this,
you have a background or overall prior
00:38:37.919 --> 00:38:40.680
use of all of them are on conventional
therapies.
00:38:40.880 --> 00:38:45.983
Half were on prior TNFs, TOCI,
abatacept and rituximab and that they
00:38:45.983 --> 00:38:51.160
were allowed to be on other therapies,
but over 50% were on csDMARDs.
00:38:51.280 --> 00:38:55.280
And what's interesting is only 6% were on
combined antifibrotic therapy.
00:38:55.280 --> 00:38:57.920
So hopefully we'll see these numbers
change quite a bit.
00:38:58.160 --> 00:39:02.601
What they were able to show is that when
you look at FVC and DLCO from pulmonary
00:39:02.601 --> 00:39:05.671
function testing,
there is actually a stabilization and
00:39:05.671 --> 00:39:09.399
maybe even a little bit of improvement
all the way up to 12 months.
00:39:09.760 --> 00:39:14.090
When you look at the high-res CT,
which unfortunately I don't have the
00:39:14.090 --> 00:39:17.078
images,
they actually all improved or stabilized
00:39:17.078 --> 00:39:19.640
for everyone treated with a JAK inhibitor.
00:39:19.640 --> 00:39:25.210
So this is pretty exciting kind of data
that's coming out and it showed that
00:39:25.210 --> 00:39:29.840
again from a joint control activity,
it actually was very good.
00:39:29.840 --> 00:39:34.232
So we hopefully we have a drug coming
down the line that's going to control all
00:39:34.232 --> 00:39:38.240
of those different domains of rheumatoid
arthritis from joints to lungs.
00:39:38.720 --> 00:39:41.320
They had, from a safety perspective,
no surprise.
00:39:41.320 --> 00:39:45.480
One patient got shingles and then another
one had ischemic heart disease.
00:39:46.960 --> 00:39:51.133
And so they were pretty excited,
as were a lot of people at ACR about a
00:39:51.133 --> 00:39:54.960
potential use now of JAK inhibitors
moving into the RA-ILD world.
00:39:55.640 --> 00:39:59.900
We need more therapies and that the data
started slowly coming together that maybe
00:39:59.900 --> 00:40:04.057
there's a new mechanism of action of JAK
inhibitors that we can use for this and
00:40:04.057 --> 00:40:07.240
that hopefully they'll be moving up in
the RA-ILD guidelines.
00:40:09.440 --> 00:40:13.320
All right, so onto antifibrotics,
which I'll leave to respirology.
00:40:15.280 --> 00:40:15.760
Thanks, Caylib.
00:40:16.280 --> 00:40:18.480
So we're going to,
do you mind if I do one question
00:40:18.480 --> 00:40:23.580
Amanda, who has an old iPhone,
I'm sure it's not an iPhone 4,
00:40:23.580 --> 00:40:25.720
but Amanda is saying that.
00:40:25.720 --> 00:40:27.320
What about TNFs?
00:40:27.320 --> 00:40:28.520
Do we just get rid of them?
00:40:28.520 --> 00:40:32.840
If someone has fibrotic ILD in their RA,
are they good guys or bad guys?
00:40:33.000 --> 00:40:36.080
And I'm kind of personally answering some
of the data,
00:40:36.080 --> 00:40:37.760
but any rapid opinion on that?
00:40:40.520 --> 00:40:44.994
Are you asking us or the general audience,
you should do a vote,
00:40:44.994 --> 00:40:46.440
You should do a vote.
00:40:46.440 --> 00:40:47.840
Yeah, we could do a vote.
00:40:47.840 --> 00:40:48.240
Yes.
00:40:48.240 --> 00:40:49.080
No, Maybe so.
00:40:49.080 --> 00:40:52.261
So asking me,
I guess I have a very high suspicion I'd
00:40:52.261 --> 00:40:55.096
be scrutinizing that patient.
Aggressively labs,
00:40:55.096 --> 00:40:59.839
imaging and clinically to see if there's
any signs of disease progression because
00:40:59.839 --> 00:41:04.120
I'd have a very low threshold to move on
to something else. Right, right.
00:41:04.120 --> 00:41:09.753
And I, and I think before we ask Ciaran,
certainly back in the day,
00:41:09.753 --> 00:41:14.723
patients with TNFs had worse disease,
longer- longstanding,
00:41:14.723 --> 00:41:20.440
higher disease activity because it was
their first advanced therapy.
00:41:20.640 --> 00:41:25.757
So multiple case reports,
particularly in in Japan and case series
00:41:25.757 --> 00:41:31.867
came out saying TNFs were giving all this
ILD and probably the retrospectoscope
00:41:31.867 --> 00:41:37.671
would say ILD is occurring because of
uncontrolled RA and the surrogate was
00:41:37.671 --> 00:41:42.559
needing a TNF because they had
uncontrolled RA for a long time.
00:41:42.920 --> 00:41:47.440
And Brian England has nicely published
from VA, which is U.S.
00:41:47.440 --> 00:41:48.000
data.
00:41:48.000 --> 00:41:54.155
It's mostly men because it's the veterans
and men hospitals throughout the US
00:41:54.155 --> 00:41:59.838
mostly men, high smoking rates,
but that if you adjust for various risk
00:41:59.838 --> 00:42:05.915
factors that the use of TNFs was no
higher on the increase incidence of ILD,
00:42:05.915 --> 00:42:11.439
no higher than the use of anything else
we could have thrown at them.
00:42:11.720 --> 00:42:16.289
So I have had to reluctantly say TNFs are
probably OK in ILD,
00:42:16.289 --> 00:42:18.280
but it's a different story.
00:42:18.280 --> 00:42:20.680
It was the question was incident ILD.
00:42:20.920 --> 00:42:24.519
So Ciaran, in your clinic,
when you're doing joint clinics or
00:42:24.519 --> 00:42:28.583
thinking about these patients,
do you say the TNF has to go when they
00:42:28.583 --> 00:42:33.286
are a patient progressing or you just say,
hey, rheumatology, treat the disease,
00:42:33.286 --> 00:42:36.480
what do you- treat the underlying act of
inflammation?
00:42:36.480 --> 00:42:38.320
What do you kind of tell us to do?
00:42:39.400 --> 00:42:41.340
Yeah,
I think that statement is definitely
00:42:41.340 --> 00:42:44.453
correct that that, you know,
treating the sort of underlying disease
00:42:44.453 --> 00:42:45.040
is important.
00:42:45.760 --> 00:42:47.701
You know,
I think in the respirology community,
00:42:47.701 --> 00:42:49.360
we've always been wary of TNF inhibitors.
00:42:49.360 --> 00:42:53.063
And I sort of take your point about the
limitations of the data we're basing that
00:42:53.063 --> 00:42:53.560
opinion on.
00:42:53.920 --> 00:42:57.811
I think we- as I've alluded to before,
we have the luxury of a lot of options
00:42:57.811 --> 00:43:01.554
now in the management of RA-ILD that I
think we're probably generally more
00:43:01.554 --> 00:43:03.600
comfortable with than the TNF inhibitors.
00:43:03.880 --> 00:43:06.221
So I,
I guess I'd be still a bit old school in
00:43:06.221 --> 00:43:10.057
that regard and would probably prefer a
bias towards one of the other agents
00:43:10.057 --> 00:43:13.494
provided that it, it, you know,
provides reasonable control of their
00:43:13.494 --> 00:43:14.839
articular symptoms as well.
00:43:15.840 --> 00:43:16.200
Wonderful.
00:43:16.200 --> 00:43:19.440
But to finish on the note,
this is a great opportunity for combined
00:43:19.440 --> 00:43:22.920
rounds and combined clinics 'cause that's
where we make those decisions.
00:43:23.800 --> 00:43:24.360
That's right.
00:43:24.600 --> 00:43:29.420
And it's a,
and it's a wonderful segue to our ILD-RA
00:43:29.420 --> 00:43:31.240
patient is fibrotic.
00:43:31.400 --> 00:43:32.760
Tell us about the data.
00:43:34.080 --> 00:43:35.520
Sure, I'd I'd be happy to.
00:43:35.520 --> 00:43:38.937
And we're going to talk about some,
some older and perhaps some suboptimal
00:43:38.937 --> 00:43:40.760
and then some exciting new data as well.
00:43:40.760 --> 00:43:42.400
So it's it's great to cover this area.
00:43:43.120 --> 00:43:45.720
I'll start with probably the the the sort
of less convincing data.
00:43:45.720 --> 00:43:48.585
And this is pirfenidone from the TRAIL-1
study,
00:43:48.585 --> 00:43:53.360
which was really the first exploration
of- of antifibrotics in this population.
00:43:54.280 --> 00:43:56.564
And again,
this was started quite a while ago and
00:43:56.564 --> 00:44:00.218
and I think was unfortunately limited by
probably not the best study design and
00:44:00.218 --> 00:44:02.959
then was, you know,
kind of bisected by the COVID pandemic.
00:44:02.960 --> 00:44:04.880
So recruitment wasn't very good.
00:44:05.320 --> 00:44:08.059
And the primary outcome was sort of a
composite of, of,
00:44:08.059 --> 00:44:11.092
of mortality and FVC decline,
which anyways, all that to say,
00:44:11.092 --> 00:44:14.761
the primary outcome was negative,
but it did show a very important signal,
00:44:14.761 --> 00:44:18.772
even with a limited enrollment that there
was a meaningful decline in the rate of
00:44:18.772 --> 00:44:19.800
FVC change over time.
00:44:20.080 --> 00:44:23.135
And if you're not familiar with looking
at sort of ILD studies,
00:44:23.135 --> 00:44:26.190
we're obsessed with FVC,
it's really the best indicator we have
00:44:26.190 --> 00:44:30.199
for sort of disease activity progression
and actually ultimately mortality as well.
00:44:30.200 --> 00:44:34.322
So we- we talk about FVC quite a bit,
but you can see this is just sliced up in
00:44:34.322 --> 00:44:35.920
sort of several different ways.
00:44:35.920 --> 00:44:38.499
But again,
you can see here the pirfenidone group in
00:44:38.499 --> 00:44:39.960
the top and and placebo below.
00:44:40.200 --> 00:44:43.560
There is a meaningful change in the rate
of decline of FVC over the study period.
00:44:43.960 --> 00:44:46.686
I'm so it suggested this probably is
probably impactful,
00:44:46.686 --> 00:44:50.514
but it's really not in common use again
because of the limitations of the study
00:44:50.514 --> 00:44:54.102
that was completed and at least in
Ontario area was not really an approved
00:44:54.102 --> 00:44:55.920
indication for use in this population.
00:44:57.840 --> 00:44:59.200
So what about nintedanib?
00:44:59.640 --> 00:45:02.282
So again,
nintedanib was also studied for use in
00:45:02.282 --> 00:45:05.734
non IPF indications and it had approval
for a long time in IPF,
00:45:05.734 --> 00:45:10.048
which as I alluded to before was really a
well understood as a primary fibrotic
00:45:10.048 --> 00:45:10.480
disease.
00:45:11.240 --> 00:45:14.733
But I think we always knew and always
hoped that we'd be able to prove that
00:45:14.733 --> 00:45:17.628
this would work in non IPF conditions
because you know, again,
00:45:17.628 --> 00:45:20.800
the principle of progressive fibrosis
was- was a very important one.
00:45:20.800 --> 00:45:23.640
And this is a sort of relatively new
concept.
00:45:24.480 --> 00:45:28.604
And so the INBUILD trial was conducted
and completed to explore the use of an
00:45:28.604 --> 00:45:32.200
antifibrotic in patients with sort of
SARD-ILD that we now call it.
00:45:32.800 --> 00:45:35.800
So patients had to have a diagnosis of an
ILD other than IPF.
00:45:36.160 --> 00:45:41.068
They had to have fibrosis on their CT and
at least more than 10% and then have an
00:45:41.068 --> 00:45:44.840
FVC of more than 45% and a DLCO somewhere
between 30% and 80%.
00:45:45.520 --> 00:45:47.896
Now this is important and,
and depending on your province,
00:45:47.896 --> 00:45:50.514
the criteria do vary a bit,
but you have to show that things are
00:45:50.514 --> 00:45:51.320
getting a bit worse.
00:45:51.600 --> 00:45:54.750
So this this indication really is for
patients who not only have fibrosis,
00:45:54.750 --> 00:45:56.640
but are showing that it's changed over
time.
00:45:56.960 --> 00:45:58.880
And you can split that up into a few
different ways.
00:45:58.880 --> 00:46:01.400
It's sort of a,
a cocktail of different factors.
00:46:01.400 --> 00:46:05.609
So you look at change on CT,
lung function change over time,
00:46:05.609 --> 00:46:06.920
or worsen symptoms.
00:46:06.920 --> 00:46:09.236
And if you mix- meet some combination of
those,
00:46:09.236 --> 00:46:13.000
you can define that this patient has
progression of their pulmonary fibrosis.
00:46:13.520 --> 00:46:16.352
And so if you meet those criteria and you
don't have IPF,
00:46:16.352 --> 00:46:20.356
then you were included for enrollment in
this study and you were given nintedanib
00:46:20.356 --> 00:46:21.040
over 52 weeks.
00:46:21.040 --> 00:46:22.560
And we looked at what happened with lung
function.
00:46:23.320 --> 00:46:24.600
So this is breaking down.
00:46:24.600 --> 00:46:26.960
So there was a whole different number of
diagnosis included.
00:46:27.160 --> 00:46:30.033
And it's important to sort of establish
the population we're talking about
00:46:30.033 --> 00:46:31.720
tonight and how they constituted the
study.
00:46:31.720 --> 00:46:35.778
So you can see in the left pie chart here,
this is the overall population,
00:46:35.778 --> 00:46:38.430
of which about 26% were SARD or
autoimmune ILDs,
00:46:38.430 --> 00:46:42.489
probably some of these idiopathic
patients or will eventually make it into
00:46:42.489 --> 00:46:42.759
here.
00:46:42.760 --> 00:46:45.893
But anyways,
but you can see that not surprisingly 52%
00:46:45.893 --> 00:46:48.800
of the autoimmune patients were those
with RA-ILD.
00:46:48.800 --> 00:46:52.679
So I think a very well represented group
and that will show itself in some of the
00:46:52.679 --> 00:46:53.720
efficacy data as well.
00:46:54.960 --> 00:46:55.880
So, So what happened?
00:46:55.880 --> 00:46:58.608
So again, as I mentioned,
patients were randomized to either
00:46:58.608 --> 00:47:00.800
nintedanib or placebo over a period of 52
weeks.
00:47:01.280 --> 00:47:04.760
And the bar chart on the column here,
this is for the the autoimmune population.
00:47:04.760 --> 00:47:07.560
And again this this effect was observed
throughout the different groups.
00:47:07.560 --> 00:47:12.153
But you can see there was a relative
reduction in decline of FVC of 58% or 100
00:47:12.153 --> 00:47:16.862
milliliters over the course of 52 weeks,
which is I think both statistically and
00:47:16.862 --> 00:47:18.200
clinically significant.
00:47:19.080 --> 00:47:21.834
Interesting that you can see that a lot
of the separation happened a little bit
00:47:21.834 --> 00:47:23.040
later over the course of the study.
00:47:23.040 --> 00:47:24.920
I don't fully understand this mechanism
here.
00:47:24.920 --> 00:47:27.280
But regardless it was in the RA
population.
00:47:27.280 --> 00:47:29.830
Again,
there was a difference of 116 mLs over
00:47:29.830 --> 00:47:32.880
the over the 52 weeks,
so similar to the entire group.
00:47:32.880 --> 00:47:34.840
And again, that was nominally significant.
00:47:37.000 --> 00:47:40.443
And looking here sort of a breakdown of
of all the different sort of autoimmune
00:47:40.443 --> 00:47:40.960
populations.
00:47:41.120 --> 00:47:44.080
I think in part we're limited by the
number who participated in the study.
00:47:44.080 --> 00:47:47.760
But you can see that of the over 80
patients with RA who were randomized to
00:47:47.760 --> 00:47:50.472
placebo or nintedanib,
looking at the forest plot here,
00:47:50.472 --> 00:47:54.347
there was a very strong signal in support
of the use of nintedanib reducing the
00:47:54.347 --> 00:47:55.800
risk of lung function decline.
00:47:56.160 --> 00:47:59.315
Again, as I showed before,
of about 117 mLs over the study period.
00:47:59.315 --> 00:48:01.952
You can see in the total group this was
the case again,
00:48:01.952 --> 00:48:04.353
limited by power in some of the other
populations,
00:48:04.353 --> 00:48:06.520
but I would argue a signal in that
direction.
00:48:06.520 --> 00:48:09.449
So beyond the scope of tonight,
I think this this drug is probably useful
00:48:09.449 --> 00:48:10.400
in other groups as well.
00:48:12.000 --> 00:48:14.586
Now importantly,
there was a lot of limitations to
00:48:14.586 --> 00:48:17.882
inclusion in this study,
which was again really done for for the
00:48:17.882 --> 00:48:20.520
purposes of showing the effect of the
intervention.
00:48:20.840 --> 00:48:24.000
But when we talk about practical
application, perhaps somewhat limiting.
00:48:24.000 --> 00:48:26.679
So you know,
patients were permitted to be on stable
00:48:26.679 --> 00:48:30.824
doses of approved medications to treat RA
or or other connective tissue diseases,
00:48:30.824 --> 00:48:33.049
but there was exclusions for very,
I think,
00:48:33.049 --> 00:48:35.879
important medications that we often use
in our clinics.
00:48:36.200 --> 00:48:40.055
So that included azathioprine,
cyclosporine, mycophenolate, tacrolimus,
00:48:40.055 --> 00:48:44.339
oral steroids - more than 20 milligrams
per day - or a combination of steroids,
00:48:44.339 --> 00:48:46.160
azathioprine and N-acetylcysteine.
00:48:46.840 --> 00:48:50.100
You also were excluded if you had
cyclophosamide within 8 weeks prior to
00:48:50.100 --> 00:48:53.451
randomization and that couldn't be
continued and also rituximab within six
00:48:53.451 --> 00:48:55.640
months prior to randomization was also
excluded.
00:48:56.520 --> 00:48:57.720
So that was a big concern.
00:48:57.720 --> 00:49:01.056
Now you were allowed to be started on
these therapies if deemed necessary by
00:49:01.056 --> 00:49:02.400
investigators during the trial.
00:49:02.680 --> 00:49:06.101
So we were allowed to explore what the
impact of these concurrent medication use
00:49:06.101 --> 00:49:07.960
was and were they confounding your
outcome.
00:49:08.560 --> 00:49:11.465
And you can see here that and it's a
little bit of a busy slide,
00:49:11.465 --> 00:49:14.504
but looking at the forest plot on the
right here. Long story short,
00:49:14.504 --> 00:49:17.991
the use of either corticosteroids at a
dose of more than 20 milligrams or the
00:49:17.991 --> 00:49:21.701
concurrent use of other prohibited DMARDs
did not have a significant impact on the
00:49:21.701 --> 00:49:22.640
effect of nintedanib.
00:49:22.960 --> 00:49:26.275
So whether or not you were or were not on
these sort of what we think-
00:49:26.275 --> 00:49:29.451
anti-inflammatory therapies,
that sort of rate of reduction of lung
00:49:29.451 --> 00:49:31.880
function decline was still statistically
preserved.
00:49:31.880 --> 00:49:34.508
So again,
a very important consideration that this
00:49:34.508 --> 00:49:38.786
drug is doing a job in parallel with sort
of other important medications we use in
00:49:38.786 --> 00:49:39.560
this condition.
00:49:45.330 --> 00:49:48.298
And then of course finishing off the
antifibrotic category,
00:49:48.298 --> 00:49:51.267
which is a super exciting news because
obviously, you know,
00:49:51.267 --> 00:49:53.889
my respirology colleagues always looked
so defeated.
00:49:53.890 --> 00:49:56.559
They had one really- drug that they used,
you know,
00:49:56.559 --> 00:49:59.690
with nintedanib and then otherwise it was
immunosuppression.
00:49:59.690 --> 00:50:03.570
So they were pretty excited with the
development of this new antifibrotic.
00:50:03.850 --> 00:50:09.883
So some of you may be familiar with the
new FIBRONEER-ILD trial looking at
00:50:09.883 --> 00:50:11.010
nerandomilast.
00:50:11.010 --> 00:50:14.922
So it's a PDE4B inhibitor,
a bit different selectivity than
00:50:14.922 --> 00:50:15.640
apremilast.
00:50:15.640 --> 00:50:19.989
So I know rheumatologists have this,
you know idea of what PDE4, it does,
00:50:19.989 --> 00:50:22.400
but it actually is different selectivity.
00:50:23.120 --> 00:50:29.180
This is looking at a randomized control
trial done by BI looking at 9 versus 18
00:50:29.180 --> 00:50:35.240
milligrams BID and then measuring primary
endpoints of 52 weeks versus placebo.
00:50:35.600 --> 00:50:40.041
And so- it's essentially showing with the
inclusion criteria, you know,
00:50:40.041 --> 00:50:45.037
had to be adults had to have a diagnosis
of ILD other than IPF and had to have a
00:50:45.037 --> 00:50:49.602
certain level of interstitial lung
disease that's significant. Following,
00:50:49.602 --> 00:50:53.056
lung function,
had to have a decreased or impaired lung
00:50:53.056 --> 00:50:57.189
function and then had to have ILD
progression and they could be on
00:50:57.189 --> 00:50:59.040
background nintedanib therapy.
00:50:59.280 --> 00:51:03.922
Exclusion criteria is obviously too
severe disease, psychiatric component,
00:51:03.922 --> 00:51:07.573
which is always the worry with the PDEs,
as is vasculitis,
00:51:07.573 --> 00:51:12.154
and then or any liver impairment or
kidney impairment or other therapies,
00:51:12.154 --> 00:51:16.920
so pirfenidone, cyclophosphamide, TOCI,
RITUX or prednisone greater than 15.
00:51:17.400 --> 00:51:19.400
The primary endpoint was FVC.
00:51:19.400 --> 00:51:23.771
Of course, as mentioned,
it's the respirologist's favorite readout,
00:51:23.771 --> 00:51:24.800
and at 52 weeks.
00:51:24.960 --> 00:51:29.790
And the secondary endpoint which is kind
of also interesting from us is acute
00:51:29.790 --> 00:51:32.640
exacerbation of ILD hospitalization or
death.
00:51:32.960 --> 00:51:37.400
And so looking at that data,
looking at the general population.
00:51:37.400 --> 00:51:42.080
So this is all of the ILD related to
SARD-ILD.
00:51:42.600 --> 00:51:46.726
And so when you look at the two different
doses of nerandomilast compared to
00:51:46.726 --> 00:51:50.370
placebo, they both did better,
but probably not a lot of difference
00:51:50.370 --> 00:51:53.639
between the two doses themselves all the
way up to 52 weeks.
00:51:54.280 --> 00:51:57.320
And when you break this down into
subgroup analysis.
00:51:57.320 --> 00:52:00.560
And so they were able to take all of the
autoimmune ILDs.
00:52:00.800 --> 00:52:04.088
And then you can see again here,
the biggest proportion of that is
00:52:04.088 --> 00:52:06.738
rheumatoid arthritis,
then scleroderma and then other
00:52:06.738 --> 00:52:07.720
autoimmune diseases.
00:52:08.560 --> 00:52:14.120
They actually were able to get a number
of about 325, of which RA there's 118.
00:52:14.120 --> 00:52:16.811
And so when they looked at that SARD-ILD
group,
00:52:16.811 --> 00:52:19.560
you can see here's the overall population
trial.
00:52:19.560 --> 00:52:21.200
So you can see the differences here.
00:52:21.200 --> 00:52:24.920
81.1 versus 67.2 as a delta.
00:52:24.920 --> 00:52:29.080
And when you look at the autoimmune ILDs,
they were still significant.
00:52:29.080 --> 00:52:32.280
So you're getting lung preservation,
which is actually pretty exciting.
00:52:32.520 --> 00:52:35.601
And the reason that's exciting is because
nerandomilast,
00:52:35.601 --> 00:52:39.330
or anyone who's used pirfenidone,
especially in autoimmune patients,
00:52:39.330 --> 00:52:43.655
the side effect profile of those drugs is
pretty hard to deal with and a lot of
00:52:43.655 --> 00:52:44.520
discontinuation.
00:52:44.720 --> 00:52:48.306
And so having a new therapy out there
that seems to be better tolerated is
00:52:48.306 --> 00:52:49.120
pretty important.
00:52:49.120 --> 00:52:50.640
So we'll talk about the safety in a
minute.
00:52:51.040 --> 00:52:56.685
The secondary endpoints were not actually
significant but trended in the right
00:52:56.685 --> 00:52:57.400
direction.
00:52:57.600 --> 00:53:02.606
And so here you have acute exacerbations,
hospitalizations or death and you can see
00:53:02.606 --> 00:53:06.480
there is a drop compared to placebo
treating with nerandomilast.
00:53:06.720 --> 00:53:09.304
And when you look at overall death
outcome,
00:53:09.304 --> 00:53:14.061
you can see here that both doses have a
decreased rate of death as time goes on,
00:53:14.061 --> 00:53:16.762
which is pretty exciting because as you
know,
00:53:16.762 --> 00:53:21.520
there's not a lot of things that we've
had in the past to change disease course.
00:53:22.160 --> 00:53:26.781
So talking about safety, so as we know,
the other antifibrotics are very hard on
00:53:26.781 --> 00:53:29.520
the patients with lots of GI side effects,
etc.
00:53:29.880 --> 00:53:33.342
And no surprise we still have some GI
side effects, but,
00:53:33.342 --> 00:53:38.383
much better tolerated and a lot less rate
of discontinuation in the treated groups
00:53:38.383 --> 00:53:41.785
versus placebo,
which is a big deal because it was very
00:53:41.785 --> 00:53:44.640
hard to keep those patients on drug long
term.
00:53:45.560 --> 00:53:47.693
It still had a bit of upper respiratory
tract infection,
00:53:47.693 --> 00:53:49.640
but from compared to placebo it looked
pretty good.
00:53:49.840 --> 00:53:53.883
And that's pretty much down all the way
of these columns from infections all the
00:53:53.883 --> 00:53:55.880
way to GI side effects, weight loss etc.
00:53:55.880 --> 00:53:57.640
They're all pretty much similar to
placebo.
00:53:57.880 --> 00:54:04.636
So that was a pretty big improvement step
forward wise from an antifibrotic kind of
00:54:04.636 --> 00:54:05.360
approach.
00:54:05.760 --> 00:54:11.080
And so we talked about the overall kind
of management strategy.
00:54:11.080 --> 00:54:15.120
So what are we actually doing now to
manage our RA-ILD patients specifically?
00:54:15.520 --> 00:54:18.494
And so I think as mentioned,
we're trying to do a better job of
00:54:18.494 --> 00:54:22.120
identifying the risk factors that are
important for high rate of progression.
00:54:22.560 --> 00:54:25.008
And so really watching these patients
closely,
00:54:25.008 --> 00:54:29.174
having a really robust screening program
- so the new guidelines that have come
00:54:29.174 --> 00:54:33.185
out in the last couple of years have
really given us better guidance of what
00:54:33.185 --> 00:54:34.800
to look for and what to screen.
00:54:35.520 --> 00:54:37.977
I mean,
Doctor Pope and myself were kind of
00:54:37.977 --> 00:54:38.480
laughing.
00:54:38.480 --> 00:54:40.822
You know, again,
we're not ordering high-res CTs in every
00:54:40.822 --> 00:54:42.720
single RA patient that walks through the
door.
00:54:42.720 --> 00:54:47.316
But I think I think we now appreciate a
lot more higher suspicion of ILD and
00:54:47.316 --> 00:54:51.673
subclinical ILD in RA patients and that
we really need to be focusing on
00:54:51.673 --> 00:54:54.299
collaborative management with
rheumatology,
00:54:54.299 --> 00:54:58.239
respirology and other specialists,
whether it's combined clinics,
00:54:58.239 --> 00:55:01.880
combined rounds to work on the management
of these patients.
00:55:02.080 --> 00:55:04.480
And it's because there's different
categories of drugs.
00:55:04.480 --> 00:55:06.947
And you know what we've kind of done in
Alberta,
00:55:06.947 --> 00:55:08.760
we've kind of conquered and divided.
00:55:08.760 --> 00:55:11.462
So the rheumatologist do a lot of the
DMARDs and you know,
00:55:11.462 --> 00:55:14.120
a little bit more of the biologics and
immunosuppression.
00:55:14.360 --> 00:55:17.947
And then we leave the respirologist to
kind of manage the antifibrotic so that
00:55:17.947 --> 00:55:21.353
we're not all stuck with special
authorization forms or not doing them all
00:55:21.353 --> 00:55:22.080
for one patient.
00:55:22.800 --> 00:55:27.046
And that the other nice thing about that
collaboration is- it's allowed us to
00:55:27.046 --> 00:55:31.511
really work closely with the transplant
lung docs who we now directly communicate
00:55:31.511 --> 00:55:35.976
with and have better access and earlier
time to referral for lung transplant that
00:55:35.976 --> 00:55:39.080
we can get better outcomes for these
patients hopefully.
00:55:39.400 --> 00:55:44.454
And that's all because you know,
RA-ILD matched RA cohorts who do not have
00:55:44.454 --> 00:55:46.880
ILD have an increased rate of death.
00:55:46.880 --> 00:55:50.880
So there is a very serious complication
of an extratricular manifestation of RA.
00:55:52.360 --> 00:55:57.749
And so while we have guidelines,
they're getting closer to overlap between
00:55:57.749 --> 00:56:02.851
recommendation versus what we do
clinically because before it was this
00:56:02.851 --> 00:56:04.360
like huge divergence.
00:56:04.640 --> 00:56:06.720
And so it's nice to see us coming back
together again.
00:56:06.720 --> 00:56:09.245
We may not all agree completely on each
part of it,
00:56:09.245 --> 00:56:12.838
but we're getting closer and it's
generated a lot of great discussion and
00:56:12.838 --> 00:56:16.771
allowed us to really start to focus on
things that we were needing to talk about
00:56:16.771 --> 00:56:17.839
with lack of evidence.
00:56:18.280 --> 00:56:23.160
It is really working to early diagnosis
and a really emphasis of treat to target.
00:56:23.160 --> 00:56:27.087
So get these patients into remission as
soon as you can because that's probably
00:56:27.087 --> 00:56:29.640
the most important thing from an RA-ILD
standpoint.
00:56:30.040 --> 00:56:34.699
And that we're really moving on to
combination therapies anywhere from like
00:56:34.699 --> 00:56:39.482
rituximab+MMF, from the EVER-ILD study.
To definitely doing combination DMARD
00:56:39.482 --> 00:56:44.387
immunosuppression with antifibrotics,
whatever that combination turns out to be
00:56:44.387 --> 00:56:47.760
based on discussion between the combined
specialities.
00:56:48.280 --> 00:56:51.800
And that is super exciting that we have
new therapies coming to the market.
00:56:51.800 --> 00:56:54.678
So, you know,
nerandomilast we'll hopefully have in the
00:56:54.678 --> 00:56:58.688
next six months to a year, you know,
having in our hands that we can actually
00:56:58.688 --> 00:57:02.646
use it and hopefully have a better
tolerable side effect profile compared to
00:57:02.646 --> 00:57:03.880
the other antifibiotics.
00:57:04.200 --> 00:57:07.176
And that, you know,
we're moving more and more to other,
00:57:07.176 --> 00:57:09.840
you know,
lung transplant and other interventions.
00:57:09.840 --> 00:57:13.917
But hopefully we get good enough that we
never have to transplant another lung in
00:57:13.917 --> 00:57:15.160
RA patient down the road.
00:57:15.160 --> 00:57:16.920
That would be our ultimate goal,
of course.
00:57:18.680 --> 00:57:22.460
And so, you know,
the guidelines that are currently
00:57:22.460 --> 00:57:26.240
published from the ACR and CHEST are
quite helpful.
00:57:26.240 --> 00:57:28.473
But when I was reading through the
journals,
00:57:28.473 --> 00:57:30.954
I really like this Harrington publication
and it,
00:57:30.954 --> 00:57:34.875
it was a combination of a guideline for
all of the different recommended ones,
00:57:34.875 --> 00:57:36.959
including Spanish and the British cohorts.
00:57:37.280 --> 00:57:41.501
And I really like this approach that they
had because it kind of more represents
00:57:41.501 --> 00:57:44.160
what we do in rheumatology as a clinical
practice.
00:57:44.480 --> 00:57:48.589
And it's using some of the drugs that we
typically tend to, to reach for,
00:57:48.589 --> 00:57:49.200
for RA-ILD.
00:57:49.480 --> 00:57:54.113
And so 1st line, 2nd, 3rd and 4th,
you can see here they're doing a lot more
00:57:54.113 --> 00:57:56.400
RITUX, abatacept and then moving down.
00:57:56.400 --> 00:57:59.578
And then if they're getting stuck,
they're moving on to the
00:57:59.578 --> 00:58:03.657
immunosuppression that only really
triggers or treats one specific domain of
00:58:03.657 --> 00:58:04.240
the RA-ILD.
00:58:04.600 --> 00:58:08.260
And so hopefully we see, you know,
a bit more of a consensus moving down
00:58:08.260 --> 00:58:11.720
towards this line of what we're actually
doing in clinical practice.
00:58:12.120 --> 00:58:14.652
And at least then we can be validated for,
you know,
00:58:14.652 --> 00:58:17.520
what we're trying to clinically achieve
with the guideline.
00:58:19.000 --> 00:58:23.418
And so, you know,
multidisciplinary care really is the
00:58:23.418 --> 00:58:28.640
backbone here because it's very
challenging multisystem disease.
00:58:29.000 --> 00:58:33.229
And so having everyone contribute with
these shared models of care and combined
00:58:33.229 --> 00:58:36.876
clinics and contributing research
education and then focusing on the
00:58:36.876 --> 00:58:41.000
patient to come up with better clinical
outcomes is really, really important.
00:58:41.240 --> 00:58:45.386
And that these relationships between the
different specialties and clear
00:58:45.386 --> 00:58:49.760
communications for decision and treatment
management is extremely important.
00:58:49.960 --> 00:58:54.800
And we've seen that directly, you know,
even in our own centre.
00:58:57.960 --> 00:58:59.960
Caylib, that is excellent.
00:58:59.960 --> 00:59:03.775
And before we have people do their eval,
Ciaran,
00:59:03.775 --> 00:59:09.770
what words of wisdom would you give the
rheumatologists who are listening on
00:59:09.770 --> 00:59:14.520
their RA patients to kind of detect ILD
in a timely fashion?
00:59:16.400 --> 00:59:16.960
Yeah, thanks, Jan.
00:59:16.960 --> 00:59:19.955
I would just draw back to that,
that slide that we looked at before about
00:59:19.955 --> 00:59:20.360
screening.
00:59:20.360 --> 00:59:23.162
I think, you know,
really understanding the importance of
00:59:23.162 --> 00:59:24.080
those risk factors.
00:59:24.080 --> 00:59:25.760
I think are they're very well established.
00:59:26.200 --> 00:59:29.967
I think in an RA patient who's presenting
with a relatively late diagnosis,
00:59:29.967 --> 00:59:32.743
who is a smoker,
I think is a person you should be very
00:59:32.743 --> 00:59:34.280
concerned and suspicious about.
00:59:34.720 --> 00:59:37.663
I would argue any, any smoker really,
you know, in general,
00:59:37.663 --> 00:59:41.588
RA or not should probably be talked to
about respiratory health and at least be
00:59:41.588 --> 00:59:44.680
considered for, for, you know,
a spirometry at the very least.
00:59:45.080 --> 00:59:48.152
And I think anyone displaying any of
those high risk features should really
00:59:48.152 --> 00:59:48.880
undergo screening.
00:59:49.600 --> 00:59:52.224
You know, and again, I think a lot of,
a lot of, you know,
00:59:52.224 --> 00:59:55.695
respirology centers will have pathways,
you know, to refer for PFTs and, and,
00:59:55.695 --> 00:59:57.875
you know,
develop relationships and pathways for
00:59:57.875 --> 00:59:58.320
screening.
00:59:58.320 --> 01:00:03.697
So I think having a very low threshold to
refer someone for testing is really the
01:00:03.697 --> 01:00:03.960
key.
01:00:05.480 --> 01:00:07.840
And and I think that's a wonderful way to
end.
01:00:07.840 --> 01:00:12.768
We do have some people writing cases in
the comments and we appreciate all the
01:00:12.768 --> 01:00:17.135
comments and we appreciate of course BI
for having this, as you know,
01:00:17.135 --> 01:00:19.880
this time to talk and discuss and
dialogue.
01:00:19.880 --> 01:00:23.920
And you'll see also the eval,
that is always appreciated.
01:00:25.200 --> 01:00:28.750
One,
one question I want to ask both of you
01:00:28.750 --> 01:00:33.269
before we close is,
is there value for me to pick up my
01:00:33.269 --> 01:00:39.080
stethoscope and listen to the bases of
the lungs of patients in clinic?
01:00:39.160 --> 01:00:42.040
I would say unequivocally yes.
01:00:42.920 --> 01:00:44.560
Yes, I would say unequivocally yes.
01:00:44.560 --> 01:00:46.545
There is,
there's sort of multiple work from,
01:00:46.545 --> 01:00:47.840
you know, all sorts of people.
01:00:47.840 --> 01:00:50.384
And I think even just being, you know,
a good clinician,
01:00:50.384 --> 01:00:52.840
putting your hands on the patient is
never a bad idea.
01:00:53.160 --> 01:00:55.700
But surprisingly,
the presence of crackles is incredibly
01:00:55.700 --> 01:00:58.240
sensitive for the presence of
interstitial lung disease.
01:00:58.640 --> 01:01:00.736
And the more you do it,
the more practice you get and the better
01:01:00.736 --> 01:01:01.640
you'll be at detecting them.
01:01:02.440 --> 01:01:04.431
So again,
that person you're not too sure about,
01:01:04.431 --> 01:01:07.234
you hear a crackle or two,
I think should raise your suspicion for a
01:01:07.234 --> 01:01:07.560
problem.
01:01:07.560 --> 01:01:09.440
So, so I would say yes, yes, yes.
Learning objectives:
Identify key risk factors, clinical manifestations, and the overall disease burden of rheumatoid arthritis–associated interstitial lung disease (RA-ILD), with an emphasis on early recognition and appropriate screening strategies.
Apply evidence-based diagnostic and therapeutic approaches for RA-ILD, including the interpretation of imaging, pulmonary function tests, and the selection of appropriate treatment options.
Collaborate effectively with respirologists to design and implement comprehensive, interdisciplinary care plans that address the complex needs of patients living with RA-ILD.
Program date: September 18, 2025
Speaker: Dr. Caylib Durand, PhD, MD, FRCPC
Clinical Rheumatologist
Peak Medical Specialty Center
Calgary, Alberta, Canada
Speaker: Dr. Ciaran Scallan, MD, FRCPC
Assistant Professor – University of Toronto
Respirology and Lung Transplant
Ajmera Transplant Center | University Health Network
Moderator: Dr. Janet Pope, MD, MPH, FRCPC
Rheumatologist
Professor of Medicine and
Member of the Division of
Rheumatology
Western University
Schulich School of Medicine
London, Ontario
Questions?
The presenters are solely responsible for developing the content of this presentation and maintaining scientific accuracy, objectivity, and balance. Any discussions of clinical practice or treatment represent the opinions of the presenter alone. This video is made available for attendees, registrants, and individuals requesting further information on this learning program.