0:00

But the problem is, like most medications, you know,

0:03

there can be side effects.

0:04

So with, uh,

0:05

disease modifying therapy in Alzheimer's disease

0:08

with using monoclonal antibodies, the uh,

0:11

side effect is aria.

0:12

Um, ARIA e, uh, stands for edema

0:16

or SoCal effusion that can develop.

0:17

So here's, uh, edema that's developed,

0:20

and here's a SoCal effusion.

0:22

And aria HH stands for hemorrhage.

0:24

Um, uh, represents micro hemorrhages

0:27

that can occur in the brain.

0:28

So you see these tiny little dots on GRE

0:30

or superficial cirrhosis.

0:34

Now, SoCal effusions, uh, with aria are thought

0:37

to represent a leakage of proteinaceous fluid from the

0:40

meningeal vessels.

0:41

And the aria E edema is thought to represent leakage

0:44

of proteinaceous fluid into

0:46

that parenchymal interstitial compartment.

0:49

Um, if we look here across the disease modifying therapies,

0:52

you can see that the incidence

0:54

of aria is much higher with Aada helm.

0:56

Uh, with chebe it's the lowest, it's 21% overall.

1:01

Um, you can see that the Aria E is about half of that

1:04

for umab.

1:05

Um, and the symptomatic aria, which is the one

1:08

that we really care about, again, much higher for Aada helm.

1:11

Um, with Umab it's 6% and then less than 3% for, uh, lecan.

1:16

So about half that of umab.

1:19

Um, symptoms of aria can be varied,

1:21

but it's often could be headache confusion, dizziness,

1:23

nausea, vomiting or visual disturbance.

1:26

And the risk factors include that initial treatment period.

1:29

So when you first go on treatment, at first three

1:31

or four months, you're at higher risk for developing aria.

1:34

Also, the higher doses are associated

1:36

with an increased incidence of Aria.

1:38

And if you are an a OE four carrier, uh,

1:41

you have an in in increased incidence.

1:43

And so, um, the label like kinumab label actually recommends

1:47

that you get tested for a POE four, um, just

1:50

so you can go over your risk, uh, with your neurologist

1:53

and have a decent idea of what your risk

1:55

of developing Aria is.

1:57

Um, so right now patients are paying out of pocket

1:59

for that genetic test.

2:01

And, you know, maybe in the future that will be covered,

2:03

but that's why not everyone is getting it.

2:05

But it is useful if you do get it.

2:07

Um, other risk factors

2:08

for Aria would be cerebral amyloid angiopathy,

2:11

and then if you are on anticoagulation, um,

2:15

you are also at a greater risk of, uh, bleeding.

2:18

Uh, aria e and a POE four carriers, uh, occurs in 5%

2:23

of heterogeneous carriers and 50% of homozygous carriers.

2:27

Again, why it's useful to get the test, um, prior

2:30

to starting medication.

2:31

But again, the good news is that symptomatic aria, which is

2:34

what we really care about, is in less than 3%.

2:37

And the Aria e nearly always resolves within one year.

2:40

In fact, typically within, uh, four months, but,

2:43

but usually always within a year.

2:44

So, uh, again, 97% are asymptomatic.

2:48

Here's a look at Aria E, um, temporal change over time.

2:52

So this was, uh, the initial, uh, development of RAE

2:56

and it, it sort of got worse

2:57

and then it started getting better

2:59

and by 300 days had resolved.

3:01

Here's another case. Here's the baseline.

3:03

MRI, uh, this is post dosing.

3:05

The patient developed RAE,

3:06

but on the post dosing follow-up,

3:08

which is typically the follow-ups are

3:10

typically done at one month.

3:11

It had completely resolved

3:12

and the patient could resume treatment.

3:14

Here's another patient. Here's their baseline.

3:16

They developed, uh, aria E post dosing.

3:19

It got a little worse at the one month stage,

3:21

and then by the two months it had gotten better.

3:24

But, uh, this is the GRE here.

3:26

Uh, you notice here at the post dosing they developed some

3:29

aria h uh, just two micro hemorrhages, just very mild.

3:32

That got a little worse over time

3:33

and was even, uh, worse again at that second follow up,

3:37

um, uh, study.

3:39

So let's talk about how you, uh, grade aria.

3:42

Um, there's mild, moderate, and severe,

3:45

and there's specific criteria for this.

3:47

So Aria e grading is all about the size.

3:50

Um, pay close attention to the slide

3:52

because we're gonna go through some, um, cases

3:55

and I'd like you to be able to choose

3:56

what you think the grading is.

3:58

So mild if fer, RAE is five centimeters

4:01

and monofocal moderate is, uh, uh,

4:04

less than five centimeters and multifocal or between five

4:08

and 10 centimeters, and that can be either mono

4:10

or multifocal, then severe is greater than 10 centimeters,

4:14

and again, can be mono or multifocal.

4:17

So once you get into multifocal, you are

4:19

by definition moderate or severe in degree.

4:22

Now Aria h unlike aria E, is all about the count.

4:25

So it's not about the size, it's about the count.

4:27

So micro hemorrhages, if you have less than

4:30

or equal to four, you're considered mild Aria h uh,

4:33

if you have between five and nine, you're moderate.

4:35

And if you have more than 10 or equal to 10, you're severe.

4:39

Now, superficial cirrhosis would be, uh,

4:42

a mild is one focal area, uh, moderate is two,

4:45

and severe is greater than two.

4:46

So you need to follow along the soci.

4:48

And, uh, c if it's all one, um, area of involvement.

4:54

Now when to suspend dose.

4:56

So the criteria is different for ARIA E and ARIA H.

4:59

But starting here with Aria E, the main thing to remember

5:02

for aria E is, uh, moderate and severe.

5:05

Because whenever the degree of aria is moderate

5:09

or severe, the dose must be suspended.

5:12

And also when the, the clinical symptoms are moderate

5:15

or severe, the dose must be suspended.

5:17

So anything in the moderate severe category, whether aria E

5:20

or sym, uh, symptoms, you're gonna suspend the dose.

5:23

If they just have mild symptoms,

5:24

you don't need to suspend the dose.

5:26

So this is very important for a neuroradiologist and,

5:30

and any radiologist that are reading this study to remember,

5:32

because it's up to you to convey back

5:35

to the referring neurologist, uh, what the degree

5:38

of severity is and whether the dose must be suspended.

5:41

So please do not forget to call the neurologist.

5:44

If you see an aria category

5:46

that would require a suspension of dose.

5:48

Now this is Aria H here.

5:50

If you're in the moderate or severe Aria H category,

5:53

you're gonna suspend the dose.

5:55

Um, but unlike with

5:56

Aria E, any patients with RAH that are symptomatic,

5:59

you're gonna suspend the dose.

6:00

So all across here, if there's symptoms

6:03

and you see any RAH, uh, again, this is over baseline.

6:07

So let's say if they had on their baseline MRI five micro

6:10

hemorrhages, uh,

6:11

after their next imaging study, once they're getting, uh,

6:14

dosed, if you see five, you're good.

6:16

But if you see anything, a therapeutic, um, you know,

6:19

micro hemorrhages that has developed,

6:20

that's when you start your aria grading.