Hello, everyone, and thank you so

much, Dr. McCall, for that kind

introduction.

Dr. Wion has done a phenomenal job

in setting the stage for

a discussion on

treatment of large vessel

vasculitis.

These are my disclosures,

and I mentioned that there are very

limited FDA approved therapies

for GCA.

It's only one, and it will be

indicated with this Red

Star.

So what I'd like to do today is to

review limitations of current

therapy for a large vessel of

vasculitis.

Then we'll talk about current

data on the use of biologics,

and then we'll discuss some emerging

treatment options for these

diseases.

So, as Dr. Wind alluded to,

giant cell arteritis is the most

common systemic form

of vasculitis in older individuals.

And there are three main concerns

with this disease.

Major items of damage

from the condition, first being

ischemia, optic neuropathy,

resulting in vision loss.

Second is vascular

occlusive events here

indicating cerebrovascular disease,

particularly in the posterior

circulation.

And other vascular events such

as formation of aortic aneurysms,

which of course, can shorten

patients survival.

So when we think about management,

we have to think about treatments in

the context of these items

of damage and how can we prevent

these?

So glucocorticoids, as you all know,

have been the mainstay of therapy

for GCA for over seven

decades.

First, patients being treated

with these agents at the Mayo Clinic

in the 1940s

where it was recognized that

glucocorticoids were able to

prevent people from going

blind, so they were able to reduce

the risk of ischemia, contact

neuropathy and patients

felt better, which is of course

always good.

And systemic inflammation.

So inflammatory markers

esr crp il six

will drop quite rapidly

following the start of therapy.

But as Dr. Ryan very eloquently

demonstrated, these agents

do not end the process

of vascular inflammation.

So as chronic vascular inflammation

continues, relapses

occur. So we reduce the

glucocorticoids and

then the subclinical inflammatory

process becomes clinically

apparent.

And patients have recurrent clinical

relapses where symptoms

with recurrent elevation of

inflammatory markers.

And even though we treat these

patients for years with

glucocorticoids and

immunosuppressive agents, they

are still at risk for vascular

complications, occlusive disease

and aneurysm formation.

And then not to mention that they

accumulate a significant

amount of damage from the treatment.

Again, in particular from

glucocorticoid.

So there's no doubt

that we need better

agents that are safer and

more effective and

have glucocorticoid sparing

properties.

And the one agent we have that's FDA

approved now is

an antagonist of interleukin six,

and that's TOCILIZUMAB.

And the FDA approval was based

on this landmark GI ACTA

trial published now approximately

five years ago by Dr. Stone

and colleagues.

And what they did in this study is

they took about 250

patients with GCA, which is

the largest study done to date,

and they randomized them into one of

four groups.

I'll

take your attention to the group in

the light blue here, because

this is what we would consider a

somewhat standard glucocorticoid

regimen that lasts for

52 weeks.

So a one year treatment with the

glucocorticoids

in the first group they used an

accelerated taper lasting

about six months.

And of course, this was set

to likely expose.

Right, a greater risk of relapses

because we were shortening the

treatment duration.

But then they added the

investigational agents.

So tocilizumab either once a

week by subcutaneous injection

or tocilizumab every two weeks

by subcutaneous injection.

Again in combination

with this accelerated or

shortened glucocorticoid

taper.

And the results are quite striking

and informative.

First, I will draw your attention

to the prednisone monotherapy

groups.

So our so-called standard

treatment with one year of

prednisone.

At the end of that one year,

less than 20% of patients

were in sustained remission.

So over 80% have

failed our so-called

standard treatment regimen.

If we give them six weeks of

prednisone, we have similarly

dismal results.

But if you add tocilizumab either

once a week or every two weeks,

you do see a significant

improvement in the proportion of

patients who are now in sustained

remission at one year, and

that's in the order of 50 to

55%. So again, this demonstrates

that there is glucocorticoid sparing

effects of this drug.

And you can see that here because

the cumulative dose is

much lower, less than half

if you provide tocilizumab for

these patients.

So again, this

led to the FDA approval of this

drug, and it is now widely

used in the management of patients

with GCA.

The risk profile

of Tocilizumab is quite

acceptable.

It's interesting that if you look at

the results of the JAK2 trial

and you look at infections and

overall serious adverse events,

it was actually numerically greater

in the individuals receiving

prednisone monotherapy.

And that reflects the greater

cumulative burden of glucocorticoids

that these individuals received.

So even though patients are reading

black box warnings on the

Tocilizumab package insert,

I do like to counsel them about

these trial results because

really, if they are receiving

glucocorticoid monotherapy,

they're going to be receiving much

more prednisone and they are

at significant risk of toxicity.

It is reassuring that in a trial

there were no deaths, no

patient had permanent vision loss.

There was one individual that had

a change in symptoms and then

responded to glucocorticoids

and tocilizumab raises some concern

regarding risk of gastrointestinal

perforations, especially in patients

with history of recurrent

diverticulitis.

And again, fortunately, this was not

seen in the clinical trial.

As you heard, giant cell arteritis

is a heterogeneous disease.

And so there are patients who

present with poorly myalgia symptoms

but have a called large vessel

inflammation.

There are patients who present with

cranial symptoms and there

are patients who present with a

blended picture of PMR and

cranial symptoms.

So does Tocilizumab work in

all these phenotypes?

And the answer is yes.

It does seem to be somewhat

attenuated in patients who have PMR

and large vessel disease.

But if we look at the risk of

flare reduction with TOCILIZUMAB,

it is quite striking, again,

particularly in those with cranial

symptoms or those with a combination

of cranial and PMR symptoms.

But it does also bring to light

that these patients with extensive

large vessel inflammation

may be somewhat more refractory

to therapy.

And that has also been seen in other

cohort studies.

So what about in clinical practice?

Our research

trainee and our clinical fellow, Dr.

Sam Mack, have worked on this

Mayo Enterprise cohort of

almost 120 patients

treated with Tocilizumab.

And again, we basically see what was

demonstrated in the GI Act trial.

Now again, this is retrospective

data, but in clinical

practice and routine clinical care,

we also see a reduction in the flare

rate with TOCILIZUMAB.

It has a glucocorticoid sparing

effect and a substantial

number of patients are able to

discontinue prednisone with

this therapy.

Of course, the patients who benefit

most from tocilizumab are those

who have glucocorticoid toxicity

or are at high risk

of glucocorticoid toxicity,

individuals with uncontrolled

diabetes, osteoporosis

and so forth.

And there's an interesting

phenomenon demonstrated in

observational studies, as well as in

the GI Act, a trial that women

tend to have a higher risk

of relapse in GCA

compared to men.

So again, they may be

particularly good candidates for

treatment with this agent.

We are concerned about visual

ischemia. Right.

So we're tapering the prednisone

rapidly in these individuals and

we're providing them with

tocilizumab.

Well, is that placing them at risk,

at higher risk of vision,

loss and blindness by doing that?

And thus far, the clinical trials

and observational data do not

suggest that. So very

unlikely to see vision loss

despite an accelerated

prednisone taper, which

is reassuring.

And again, this has been seen in the

clinical trials, as well as

some observational data from

Europe and from the U.S..

There are situations, though, where

the risk of tocilizumab

may outweigh the benefit.

First of all, I'm concerned

about patients where the diagnosis

is uncertain, and we do encounter

patients with so-called biopsy

negative GCA.

Even more troublesome is if they are

biopsy negative and imaging

negative, and the diagnosis

is made entirely on

clinical grounds.

And here's an example of a patient

with a PET scan that was

reportedly positive for a large

vessel, vasculitis, and this

turned out to be an intra sarcoma.

So you can imagine this individual

is not going to respond to

tocilizumab in

patients who have recurrent

infections.

Again, if there is a history of

recurrent diverticulitis,

those might not be good candidates

for tocilizumab.

Some individuals may develop

liver function abnormalities, and

we've had a few patients with

including development of jaundice.

And so this needs to be monitored.

And then some individuals may

develop side opinions.

Now, in many patients, these are

mild and may respond

to reducing the dosing interval

of tocilizumab.

But again, it is important to

monitor these.

So when we think about the current

algorithm for the treatment of giant

cell arteritis, this reflects our

practice and is consistent

with current published guidelines.

Basically, if a patient has GCA

with vision loss, then intravenous

pulse dose glucocorticoids

are recommended.

In the absence of visual ischemia,

then we initiate high dose

oral glucocorticoid generally

prednisone and we assess

is the patient a good candidate

for a tocilizumab?

We feel that we should educate

the patients about the availability

of this glucocorticoid sparing

agent. And again, if there is

an acceptable risk benefit

profile, then we initiate

tocilizumab.

This would allow an accelerated

glucocorticoid taper,

shortening the glucocorticoid

treatment to six months

and hopefully remission is

maintained.

If not, and there are recurrent

relapses, then we may consider

the patient for investigational

therapy.

If for whatever clinical reason

the patient has not started on

tocilizumab, then of course we

continue with a very gradual

glucocorticoid taper, often

in excess of a year,

and as we taper the prednisone, the

patients may relapse and many

of them do.

And then again we reassess

the candidacy for treatment

with Tocilizumab.

So we talked about, you know, the

patients feel about are there

inflammatory markers improve?

We do reduce their risk of

blindness. But what's happening on a

vascular level

and I know Dr. Koster will talk more

about imaging studies in GCA,

but this is an interesting cohort

study from Italy.

Dr. Muratore and colleagues

conducted this rigor study

where they looked at PET scan over

time and they

assessed patients who are treated

with prednisone, patients

who are treated with methotrexate

and prednisone or

prednisone and tocilizumab.

And they did see that in all three

treatment regimens there was

a reduction in vascular inflammation

as assessed by patch c.T.

Perhaps the reduction in vascular

inflammation was even more

accelerated in those receiving

tocilizumab.

But as you can see, it also took

time for this to improve.

And there were a number of patients

where subclinical inflammation

or I should say radiographic

inflammation persisted

despite treatment with

any of these three regimens.

So again, they did see a

glucocorticoid sparing effect.

They did see a beneficial effect

from a pet vascular

standpoint.

But again, not all patients

had resolution of vascular

inflammation.

And then what happens?

So again, Dr. Wayne mentioned,

you know, these therapies are not

curative.

Right. So the question is, how long

do you continue patients, whether

it's glucocorticoids or tocilizumab?

And we know that if you stop

tocilizumab a little bit too early,

patients are likely to relapse.

So in the Stone article, patients

were treated for a year

and then followed for another two

years and more than

half then relapsed.

So obviously, if you treat for one

year the risk of relapse,

you know, one year and you

discontinue, then the risk of

relapse is substantial and

other studies have shown a lower

risk of relapse, but that's because

they followed the patients for

a shorter amount of time.

The time to flare after

stopping tocilizumab is quite

variable

and.

Really oftentimes if the patient

relapses, then you are able

to re initiate tocilizumab

and you do obtain a favorable

clinical response.

So in practice we treat patients

for a minimum.

Again, a really the

least would be one year, but

oftentimes in clinical practice we

go to 18 to 24

months. We do try to reduce

or taper the tocilizumab

and watch for the clinical response.

Again, if patients relapse, we do

restart therapy and there

is some reassuring data

that even if we treat patients for

several years, there are no

unexpected safety signals.

As you can imagine, a lot of

patients relapse with symptoms

of poly myalgia, rheumatic,

but others may have cranial symptoms

or even other vascular

manifestations.

What about the future?

What is next for the treatment of

GCA? There are some promising agents

on the horizon, one

of them being avatars, left avatars

that blocks T-cell stimulation.

And so targets.

Those immunologic pathways that were

nicely outlined by Dr. Weyand.

And in this randomized pilot

trial, a small study with 49

patients.

There was a signal of efficacy

where patients treated with

appetiser were more likely

to remain relapse free

compared to those receiving placebo.

There is some cutting edge data.

This trial has not

yet been published, but every Lyma

Mab is an inhibitor of

GM, CSF and blocks

macrophage activation.

A short trial on a relatively

small number of patients, but again,

a signal of efficacy

where this agent is able to increase

the proportion of patients in

remission.

Emerging data with interleukin 17

inhibition. This was presented at

the American College of Rheumatology

meeting this past fall.

Again, a nice treatment signal

with a higher rate of remission

in patients receiving SEC in MAB

compared to placebo.

So we eagerly await

a validation of these

data and larger trials.

But this is now opening

the the toolbox

really to have other agents

that we are able to use for the

treatment of giant cell arteritis.

Another interesting story is

and we've heard quite a bit at this

meeting about Jacques inhibitors.

But approximately six years ago, we

started this

project really

encouraged by the data that Dr.

Ryan generated from her lab and

from her Avatar murine models

demonstrating that JAK

inhibition is really able to

target and improve vascular

inflammation in those preclinical

models. And so we designed this

open label pilot study

utilizing Baricitinib for

patients who have already had

relapsing GCA.

So these are patients who are

more refractory to therapy

and we treated them again in an open

label fashion with baricitinib.

In addition to a standardized

and accelerated prednisone

taper.

The results of the study were just

published a few days ago in Annals

of Rheumatic Diseases, and the study

was led by Dr. Coster.

But very encouraging

data in that of

these 15 individuals,

one was

removed from the trial due to

chronic kidney disease, but 14

patients were treated during the

trial and only one

of those individuals relapsed

while on Baricitinib.

So this is again open label.

There is no control arm, but

considering the patient phenotype

of relapsing disease,

this is an encouraging signal.

There were no unexpected safety

signals, even though of

course, again, this is a small

sample size and we are aware

of the potential complications

related to jack inhibition.

But patients were able to come off

prednisone, their inflammatory

markers improved.

And again, most of them did

very well on this drug.

Indeed, several of them actually

relapsed following discontinuation

of Jak inhibition.

Of course, larger studies,

prospective randomized trials

would be necessary to really

understand where

this drug might fit in the treatment

for GCA.

Briefly, I'll mention the recently

published ACR guidelines for

the treatment of GCA.

And again, they recommend high dose

oral glucocorticoids, which is of

course not surprising,

and they do recommend the

use of tocilizumab and

in combination with glucocorticoids

if if there is an acceptable

safety profile

and then they recommend, you know,

again, which are the patients who

are most likely to benefit from

a steroid sparing agent?

Those are patients with relapses.

And there is some emerging evidence

that those with large vessel

involvement, so extensive aortic

inflammation, perhaps in the

subclavian and axillary vessels

may benefit,

particularly from the addition of

tocilizumab in.

So I'll switch to

discussing osteoarthritis

for a little bit here.

This is a very challenging

disease.

It's a condition affecting young

women, often during childbearing

age in their thirties.

There is this very

aggressive, inflammatory process

with this muscle hypoplasia

that results in standard of disease,

especially involving the aortic

arch branches.

So you can imagine they often have

cerebrovascular ischemia.

They have upper extremity

coordination and other

complications.

We treat them with glucocorticoids,

but those are really quite

ineffective for this disease.

So a very small proportion

of patients are able to achieve

remission with glucocorticoids

alone.

We provide them with a with one

of these immunosuppressive agents,

methotrexate or a thigh

heparin or mycophenolate

or le fluid amide.

But it is embarrassing to realize

that we are basing this on

open label trial data,

often including trials of

less than 20 subjects.

So again, this speaks to the rare

nature of this disease

and to the paucity

of trial data in this disease.

And even if we give them these

agents, patients have frequent

relapses, they progress,

and they often end up requiring

vascular surgery.

So there has been interest in the

use of biologics.

Again illustrated here is a patient

who at onset so this is

at their first clinical presentation

they often already have widespread

vascular damage again primarily

involving the aortic arch

branches.

So TNF inhibitors have now

been shown to be useful,

to be effective for this disease,

particularly in patients

with refractory disease.

The issue is that it's all based on

retrospective cohort studies.

So there are no prospective

clinical trials of TNF

inhibitors in patients with TAKEDA.

So most of them respond

either completely or partially.

But again, relapses are common,

so these are not the answer.

But some of the more compelling data

is again, observational.

But this is a study

demonstrating

that what happens to these patients

in terms of vascular progression.

So how many patients remain free

of vascular progression

according to our treatment?

And if we give them prednisone only,

you'll see that the majority

are have had vascular progression.

So almost none of them remain

free of vascular progression.

If we give them immunosuppressive

agents, we do a little better.

But if we give them CNF inhibitors,

then the majority of patients

are going to mean are going to

remain free of

vascular progression.

So this is compelling data, but

it is observational.

So then because of the efficacy of

tocilizumab in giant cell arteritis,

of course there was interest in

using this for Takeda

soon.

This is a prospective trial

conducted in Japan.

They took patients with relapsing

Takeda, so they randomized

them to placebo or

tocilizumab and they looked

at the time to relapse

of Takeda soon.

The trial results were

underwhelming.

So if you look at the initial

intent to treat analysis,

this did not meet statistical

significance.

If you use a looser

statistical analysis and you only

analyzed patients who received

the drug, but then you're not

including patients who dropped out

for various reasons, you

see a hint of efficacy.

And so this suggests that perhaps in

a subset of patients with Takeda,

also, Tocilizumab

may be an effective treatment

option.

Again, I draw your attention to the

size of the trial

with less than 20 subjects in

each arm. So this is somewhat

preliminary and requires

confirmation.

The Europeans

got together and assembled a large

cohort of patients with TAKI, also

over 200.

But now this is observational

data and they

looked at whether the patients

received TNF inhibitors

or TOCILIZUMAB.

Again, with observational

retrospective data, you have larger

numbers here and they

demonstrate that there was no

difference in efficacy, no

difference in relapse rate or

retention rate of these drugs.

So somewhat encouraging data and

in terms of the success rate,

but again, this is not prospective

and not randomized.

One of the concerns with Tocilizumab

is that Tocilizumab does an

excellent job of normalizing

inflammatory markers.

So our one of our main

tools, CRP measurements

is now gone because patients

on Tosi are going to have normal

inflammatory markers.

And we and others have published

the concern in clinical practice

that the normal CRP may

lead to false reassurance

on the part of clinicians, and

yet patients may have progressive

vascular damage.

And this is an example of a patient

who developed a new carotid

lesions. And we have seen other

vascular complications

in patients who seemingly are

doing well and have a suppressed

systemic, inflammatory response.

So certainly something

to be aware of with this drug.

When we look at current published

guidelines, the European guidelines

have a nice algorithm regarding

treatment for accuracy.

They again recommend starting high

dose glucocorticoids

in combination with an

immunosuppressive agent.

Again, knowing that glucocorticoids

have such a low success rate in

this disease, they advocate

right away to start a conventional

immunosuppressive agent.

Of course, then we taper the

glucocorticoids

and if there is a relapse,

then we treat the relapse with a

glucocorticoid.

But then we want to introduce

a biologic, either

TOCILIZUMAB or a

TANF inhibitor.

Now, the European guidelines

recommend either or

the American College

of Rheumatology Guidelines favored

TNF inhibitors over

TOCILIZUMAB.

Now again, the TNF inhibitors have

not been evaluated in a prospective

clinical trial, but there is ample

observational data

and greater experience

with the use of these drugs in

clinical practice.

Again, that perhaps

there may be some superiority

of these agents over tocilizumab.

But they still also,

you know, include tocilizumab

in their in their guidelines as a

treatment option.

Antiplatelet therapy is often used

in Torque. Also, here is one

of the major concerns with this

disease damage from cerebrovascular

disease. And so we often add

antiplatelet therapy

and current guidelines also

advocate for antiplatelet therapy,

particularly in the context of

cranial or vertebral

basilar involvement.

And again, this is quite common

in these patients.

Unfortunately, most of

the patients with taki also

arteritis because of our failure

to control the disease with medical

therapy do go on to

require vascular intervention.

Oftentimes vascular bypass

surgery for arterial stenosis

either due to a cerebrovascular

disease persistent

clot occasion, renal vascular

hypertension or aneurysm

complications.

It's important to emphasize

that the best outcomes of

surgical intervention occur

if the patient is in remission.

So we do try to

very carefully assess patients,

assess them for disease activity,

and if their disease is active,

to try to optimize their medical

therapy before they go to surgery,

because, of course, we want them to

have good outcomes from their

disease. Here's an example of a

patient who underwent bypass

surgery to their subclavian

because of persistent arm

altercation.

And if patients have active disease,

then we certainly want to avoid

manipulating these arteries with

angioplasty or stent or surgery.

And we really want to treat them

medically to reduce the

vascular inflammatory process

before we involve our

vascular surgery colleagues.

So in summary, I hope that I have

demonstrated to you that the

treatment landscape and large vessel

vasculitis is changing

and we now have biologics

in our toolbox.

So that allows us to use less

glucocorticoids, hopefully improve

quality of life of our patients

by reducing the burden

and the toxicity of glucocorticoids.

Of course there are a number of

unmet needs and

research in these diseases

continues.

I thank you for your attention and

I'm happy to take questions later.