So I will be reviewing treatment for
the two major forms
of large vessel vasculitis.
Those being giant cell arteritis
and talk chaos to arteritis.
So giant cell arteritis is
the most common form of
systemic vasculitis
generally seen in older individuals.
And there are really three
main items of damage
that keep us quite
concerned about this disease.
One being ischemic optic neuropathy,
which may result in
vision loss and blindness.
The other, the risk for stroke
particularly and the for
T bro bachelor territory.
And the third is a later
or long-term complication of the disease,
which is development of aortic aneurism.
And of course, giant cell arteritis can
also present
with peripheral arterial disease,
sometimes, oftentimes
in the upper extremities,
and rarely even
involving the lower extremities.
Now historically or for
over seven decades or so,
we have used glucocorticoids for
the treatment of inflammatory
vascular diseases.
And we know that there are
benefits from the use of
these drugs today, prevent blindness.
Patients feel better.
They often have constitutional symptoms,
myalgias and other vascular symptoms,
and their symptoms do improve.
We are able to suppress
systemic inflammation with these agents.
On the other hand, glucocorticoids ofcourse
have a long list of adverse effects.
Despite our best efforts a treatment,
patients frequently
experienced disease relapses
as we tried to reduce therapy.
And again, despite
our best efforts that treatment,
patients continue to
experienced vascular complications,
including for example,
stenotic disease and subclavian
and axillary arteries and aortic aneurisms.
So the gold standard diagnostic tests for
giant cell arteritis remains
biopsy of the superficial temporal artery.
And what we're looking for is
this transmural inflammatory process.
The artery responds to
this inflammatory insult with
hyperplasia of the intima layer,
which results of course in
the vaso occlusive
consequences of this disease.
So over several decades we
have been able to understand
the immunologic players in this process.
And we now recognize that there
are activated dendritic cells
that pull in T cells
that are activated macrophages that
fuse to form giant cell is all
occurring in the arterial wall,
which in normal individuals
should be an immune privileged site.
So there is breakdown of tolerance and
that infiltration of these cells
in the arterial wall.
We have also learned that one of
the key players that facilitates
crosstalk and knees in
this inflammatory process is
the cytokine interleukin-6.
So essentially after seven decades or
so of looking
for an effective glucocorticoid
sparing agent for GCA.
It was identified
that interleukin-6 inhibition
is a key element
that can be utilized as treatment.
So the monoclonal antibody toast Elysium AB,
which you may have heard
about quite a bit during
the COVID pandemic because it is
used also for treatment of COVID.
This monoclonal antibody was evaluated
in a landmark clinical trial
of giant cell arteritis now.
And these rare diseases,
a clinical trial with 150 patients
is considered one of
the largest trials to date.
Patients were randomized to
one of four treatment arms.
Either a 26 week course of glucocorticoids,
a one-year course of glucocorticoids,
or a six-week course of glucocorticoids
in combination with socialism AB,
which is given as a subcutaneous injection,
either ones or once
weekly or every two weeks.
The results of the trial
were very interesting.
It was demonstrated that if you treat
patients with monotherapy glucocorticoids,
your success rate,
meaning having them remain and
sustained remission
over a period of one year.
Your your CR success rate is very low.
You can see here with less than 20 percent
of patients remaining and remission,
whether you give them six months or
one year course of glucocorticoids.
And of course that in of itself is
already accumulating substantial toxicity.
But if you then add on
this interleukin six blocker,
you are able to achieve
a much higher proportion of
patients will remain in
remission at one year.
So this landmark clinical trial
led to the FDA approval.
This biologic, again,
this is the only biologic that's
approved for the treatment of
giant cell arteritis in combination
with a tapering dose of glucocorticoids.
Of course, we want to evaluate
the adverse effects of
this therapeutic agent than
it was actually seen.
That interestingly, the patient's
on a monotherapy,
glucocorticoids actually had
a greater number of adverse events,
again, related to glucocorticoid use.
And it was actually lower.
And those who received the study drug,
mainly because these individuals also
received a reduced amount of glucocorticoids.
During the trial. Fortunately, there were
no individuals who had permanent vision loss.
There is a concern with
this twist holism AB drug where patients who
have recurrent diverticulitis may be
at risk of gastro intestinal perforations.
Again, this is a rare concern and
fortunately none were seen during
the one-year clinical trial.
Of course, not every patients might be
a good candidate for this biologic.
We generally do not initiate a biologic
if the diagnosis of
a large vessel vasculitis is uncertain.
If patients have recurrent infections,
if they are at higher risk
of gastro intestinal perforation.
The drug may also
affect liver function and therefore we
monitor this closely and we avoid
its use in those with active liver disease.
It may also cause cite
a PDS and again therefore would be contra
indicated in patients who may have
baseline site opinion as I
have this picture here to again
emphasize that when the
diagnosis is uncertain,
we want to avoid and introduction
of immuno therapeutic agents.
This was an individual where
their PET scan raised
concern for large vessel vasculitis,
not respond to immunosuppression.
And this was because the,
the correct diagnosis actually it was
an anxious sarcolemma of the aorta.
So again, we have to
keep a broad differential,
particularly when patients are not
responding to therapy as expected.
So we now have an updated
algorithm as to how we treat
giant cell arteritis and
then patients with visual ischemia.
We treat with intravenous
high dose methylprednisolone.
And those who do not have visual ischemia,
we initiate high dose glucocorticoids,
generally prednisolone 60 milligrams daily.
But then we assess all patients as whether
they are candidates for
initiation of a biologic drug.
If we do start socialism app,
we then accelerate
the glucocorticoid taper and again
aim to provide
a glucocorticoid sparing effect
with this biologic.
If the patient is
not a candidate for it twists
holism app therapy then width into
new standard glucocorticoid taper.
But if the patient has relapses, then again,
we assess them as to whether they are
candidates for treatment with socialism app.
There are now national
guidelines that have been
formulated very
recently and published last year.
And the national guidelines do recommend
the use of glucocorticoids
with tos holism AB,
over using glucocorticoids alone, again,
emphasizing the importance of
trying to provide a steroid
sparing agent to reduce
the risk of glucocorticoid toxicity.
In particular, of course,
we want to utilize
this novel agent in
patients who have recurrent relapses
because they are the ones that
are going to experience
most use of glucocorticoids
and therefore associated adverse events.
And patients who have what we
call large vessel involvement,
meaning when there is evidence of a or Titus,
when there is evidence of aortic arch or
other territories
being involved by the disease.
I'll talk a few minutes about
Takeda also arteritis.
This has some similarities
to giant cell arteritis,
but is much more rare.
It affects one to two per million per year.
It generally causes disease,
occlusive disease and
the aortic arch branches,
as you're seeing here,
There's this very profound
intimal hyperplasia
that results in the luminal compromise.
We diagnosis generally by
imaging studies shown here is
a PET CT demonstrating FDG uptake and
the wall of the aorta
and then the carotids again,
highlighting the inflammatory nature
of this condition.
And of course, if the patient presents with
arterial occlusive disease and
the context of an inflammatory process.
We then treat with glucocorticoids
and often use conventional
immunosuppressive agents.
But even in this disease,
we have now entered
an era of biologic therapy.
And the biologics we use the most often and
disease are the inhibitors
of tumor necrosis factor.
Interestingly, even though there are
similarities between giant cell arteritis and
talk chaos to the clinical trials in GCA were
unsuccessful with the use of
TNF inhibitors. Under the hand.
Tnf inhibitors appear to have
a role in the treatment of Takahashi.
Particularly in patients who
have disease that is
refractory to
our conventional
oral immunosuppressive agents.
It is humbling to note that
because this is a rare disease,
there have been no prospective
randomized trials
of these agents and talk chaos through.
So their use is based
entirely on retrospective cohort data.
That should, that suggests
that the majority do respond,
but they may still experience relapses.
One of the difficult things with takeaways.
This is a patient who
already at the first diagnosis already has
significant vascular damage with
occlusive disease involving
again aortic arch branches.
So we see a lot of damage, right?
A disease onset and
patients continue to accrue
damage as they progress with this disease.
It is reassuring to
see that these TNF inhibitors
now maybe our best
chance at halting disease progression.
So this is observational data.
But what the investigators were
able to demonstrate is
that if we treat
these individuals with TNF inhibitors,
the majority of them are able
to be
maintained without new vascular lesions.
So, so the best chance of keeping
patients from having new vascular lesions,
new vascular occlusive disease
is by treating with these TNF inhibitors.
On the other hand, if you use
conventional immunosuppressive agents
or glucocorticoids alone.
Patients are much more likely to progress
to progressive vascular occlusive disease.
There is some interests, again,
in the use of Tesla is a map.
Again, this is in contrast.
So in giant cell arteritis,
this IL-6 inhibitor appears
to be remarkably effective.
In distinction to that.
In takeaway osteoarthritis,
the trial with socialism,
I have actually did not
meet its primary endpoint.
Now again, this is a rare disease.
You will see that the two arms of
the trial included 18 patients on placebo,
18 patients on active drug, again,
highlighting how rare diseases and how
small the trials are with these agents.
The primary endpoint of this trial
that was conducted in Japan was
time to relapse and it's actually not met.
They did see some signal of efficacy
and a subset of patients.
But, but it is not as effective as
we see in that giant cell arteritis.
There was an interesting phenomenon
when you treat patients with this drug
because it is so effective
at inhibiting interleukin-6,
it essentially normalizes the
patients inflammatory markers and
therefore removes
that biomarker of disease activity.
So we and others have
documented and published that
there are individuals who
have disease progression despite
suppression of their inflammatory process,
at least as far as we
can pick up systemically.
There are also national
and international treatment guidelines
for top-k osteoarthritis.
They include recommendations to treat with
glucocorticoids as well as
a conventional immunosuppressive agent.
But in patients who have progressive disease,
than it is recommended to
introduce a biologic agent,
either an interleukin 6
inhibitor or a TNF inhibitor.
These are European guidelines and
the US guidelines favor
the use of TNF inhibitors.
Again, even those, these have not been
evaluated respective clinical trials,
there is ample observational data
and use in clinical practice
to demonstrate that
TNF inhibitors may be our best chance to
halt the disease progression
that we see and talk chaos, arteritis.
So in summary,
I hopefully have shared with you
that the landscape of treatment for
inflammatory vascular diseases as changing.
We have now the opportunity to use
targeted monoclonal biologic agents
for the treatment of these diseases.
And particular, we routinely use
an interleukin 6 inhibitor
for patients with giant cell arteritis.
And we often utilized
TNF inhibitors for a takeaway osteoarthritis.
Obviously, you will have
a number of unmet needs.
These patients are at risk for
substantial morbidity.
And talk I also even
potential premature mortality.
You're seeing here a young woman who had
a devastating cerebrovascular accident due to
the arterial occlusive disease
from top to osteoarthritis.
So we definitely have,
have work to do in these diseases.