HLA-Mediated Immune Reactions (Skin Rash)

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From the course by Vanderbilt University

Case Studies in Personalized Medicine

179 ratings

Vanderbilt University

Case Studies in Personalized Medicine

179 ratings

Learn how advances in biomedicine hold the potential to revolutionize drug development, drug treatments, and disease prevention: where are we now, and what does the future hold? This course will present short primers in genetics and mechanisms underlying variability in drug responses. A series of case studies will be used to illustrate principles of how genetics are being brought to bear on refining diagnoses and on personalizing treatment in rare and common diseases. The ethical and operational issues around how to implement large scale genomic sequencing in clinical practice will be addressed. After completing this course, learners will understand 1. The ways in which genetic variants can contribute to human disease susceptibility 2. How to choose among drug therapies based on genetic factors 3. That the functional consequences of the vast majority of genetic variants discovered by modern sequencing are unknown. This course is targeted primarily at physicians 5+ years out of training. Other healthcare providers, medical/health sciences students, and members of the public may also be interested. Course launches January 15, 2016. * The information presented in “Case Studies in Personalized Medicine” is offered for educational and informational purposes only, and should not be construed as personal medical advice. If you have questions or concerns about a medical matter, please consult your doctor or other professional healthcare provider.

From the lesson

UNIT 3: CASE STUDIES IN PERSONALIZED MEDICINE, PART 1

In Module 5 we will begin to discuss specific cases as these apply to personalized medicine. We will first look very closely at a case of familial hypercholesterolemia as we investigate how we use genomic medicine to move from a rare disease to a common medication, using genomics to find new drug targets, and a discussion of the side effects of statin therapy. In Module 6 we will look at a collection of "high risk pharmacogenetics"cases that illustrate adverse reactions due to drug metabolism and variable drug responses.

HLA-Mediated Immune Reactions (Skin Rash)9:55

Long QT Syndromes, Part 115:49

Long QT Syndromes, Part 218:17

**Inside VUMC: Studying Cardiac Arrhythmias in Cells4:09

A Second Heart Attack a Month After a First15:24

Headache During Venlafaxine (Antidepressant)16:50

Respiratory Arrest After Tonsillectomy10:15

A Bleeding Complication 5 Days After Starting Warfarin21:53

**Inside VUMC: Genotyping1:47

Drug Metabolism and Variable Drug Responses – Four More Examples17:17

Meet the Instructors

Dan Roden, M.D.
Professor of Medicine and Pharmacology
Assistant Vice Chancellor for Personalized Medicine

[MUSIC]

This module deals with immune mediated drug reactions which are among

the most feared and actually among the increasingly well understood reactions.

The story starts with a 16 year old girl who has difficult to manage epilepsy.

A drug called carbamazepine,

one of the relatively standard anti-epileptic drugs is started.

And within a week, she develops a really severe adverse drug reaction.

That it basically involves sloughing of the skin.

This is not her.

This is other example and

it shows the sloughing of the skin around the tongue and on the face.

This is called Stevens-Johnson's syndrome and it's more severe cousin

is also known as Toxic Epidermolysis syndrome.

Very rare.

Potentially fatal.

Treated like a burn basically.

The story around individual susceptibility starts with a report from

a chinese group in nature that looked at

specific HLA variants, and I'll come back to what that means in a moment.

But they found a set of genetic variants in

this set of genetic variance that mark risk for

Stevens-Johnson syndrome during treatment with carbamazepine.

And the specific variant that they were interested in

is the variant called B*1502.

And you can see on the bottom of this slide that this confers odds ratios

that are 2500 or 900.

So we've talked about odds ratios.

This is a small set of patients with enormous odds ratios.

So this is pretty convincing.

So I'm going to say a little about HLA.

HLA is the most highly polymorphic locus in the entire human genome.

There is a series of individual genes in the HLA locust that are shown here.

The nomenclature is shown on the bottom there, A alleles, B alleles, and

then there are star, the major type and the major subtype.

So B*1502 is the risk allele.

For carbamazepine induced Stevens-Johnson syndrome.

What HLA proteins do is they take small peptides and

the present them to T cells.

And the small peptides are usually derived from things like cancers or infections,

and they allow RT cell systems to respond to those challenges by

destroying the particular cell that is expressing the foreign antigen.

We'll come back to that as a potential mechanism in a moment.

So that was carpimezapine in an East Asian population.

Other investigators across Europe have looked at carbamazepine-induced

Stevens-Johnson syndrome in Caucasian populations and you can see with 22 cases,

a tiny number of cases and a very large number of controls,

these are population controls not necessarily exposed to carbamazepine,

there's a very strong signal again, at the north end of chromosome six.

That's typically in the HLA region.

What's interesting about this signal is that it's not B*1502, but it's A*3101.

So that suggests that in different ancestries,

the risk alleles may be different.

An important generalizable lesson across genetics and pharmacogenetics.

Another really,

really high profile example is with the antiretroviral drug abacavir.

In early 2002, a group from Perth,

Australia reported that among patients with abacavir hypersensitivity reactions

there was a really, really much increased frequency of the HLA-B*5701

alele compared to patients who had received Abcavir and

who did not develop skin reactions.

With odds ratios that are again very, very high, up to 822.

Four combinations.

So one school of thought would say let's start

to test patients who are receiving carbomezopine or abacavere for

these alleles, and avoid those drugs in patients who carry risk alleles.

Another school of thought says, well, we have to have randomized clinical trials.

Now, we'll come back to the issue of when is it appropriate to demand

a randomized clinical trial or not, but the group in Perth went ahead and

organized a randomized clinical trial and the results are shown here.

The design of the trial was basically to take 2000 patients

who were starting antiretroviral therapy and who were targeted for

Abacavir as part of that initial therapy.

A 1,000 of them had genotype guided therapy that is they had testing for

B*5701 and if they had the riscollio, they would not get abacavir.

The other group went ahead and got normal regiment that included abacavir.

You can see that the incident of skin rash was around 6% in the control group and

around 3% in the genotype guided group.

So you would say, well, the genotype guided treatment does seem to

reduce the incidence of this potentially fatal adverse drug reaction, but

doesn't get rid of it.

But what these investigators had done that was incredibly important for

this study was that they had developed a method to actually look at each skin rash,

assay the skin, and understand whether the rash was due

to abacavir and abacavir immediated immune reaction or not.

And when they did the immunologic testing

every single patient who got abacavir genotype guided

with a skin rash turned out to have a skin rash from something else.

So there were actually zero cases

of abacavir related skin rash among the genotype guided treatment and about 3% of

cases that were really confirmed Abacavir related skin rash in the control group.

So based on these kinds of data, abacavir genetic testing has now

become pretty routine across the world.

How does this work?

One thought is that abacavir, or drugs like it combined

with antigens that we have floating around in our bodies to which we become tolerant.

There are proteins floating around all the time.

Abacavir and the protein together create what's called a neoantigen and

that is recognized as foreign.

And in some way, the T-cells then attack the foreign antigen.

Now an alternative therapy, an alternative theory is shown in this particular slide.

The idea is that abacavir slides into

the HLA-B*57:01 version of HLA.

That's a particular protein whose job in life is to present a particular

peptide to the T cell.

But when abacavir has slid into the binding groove for that particular HLA.

It changes it's confirmation.

And, It changes it in a way that gets proteins that are ordinarily not

recognized by the T-cell and the T-cell then attacks those particular cells,

and for some reason the culprit protein whatever it is lives in the skin.

Of course the reaction is not necessarily always confined to the skin.

It can include the GI tract, include the lungs.

In which case people would present with diarrhea or pneumonia.

And we think this is what's going on.

So they're competing theories, but it's clear that there's something about

the structure of HLA-B*57:01 and the way in which it combines with

abacavir that changes its function in such a way as to allow this reaction to occur.

As I said before, regulatory agencies around the world have relabeled abacavir

to really strongly recommend genetic testing before the drug is started.

And most importantly professional societies have gone along with this

particular recommendation so

this has become relatively routine in the HIV therapy world.

Again, let me summarize by saying that immune reactions are an important

cause of rare, but severe, drug reactions.

We're beginning to understand the mechanisms and much more importantly.

We're beginning to identify specific molecules with specific genetic variants

in which risk is dramatically increased.

And that risk is pretty easy to show in even very, very small cohorts.

So just like with the syntha statin story, this kind of story

raises the possibility of everybody knowing what their HLA genotype is.

And when a drug is prescribed we say well avoid this particular

drug because you're at higher risk for developing this severe drug reaction

compared to a person that doesn't have that risk allele.

And again as we've seen already, and as we'll see increasingly,

some of the risk alleles are confined to specific ancestry.

So just because we know what the risk allele is that

are Caucasian population doesn't mean that the same risk allele

will be present in an African population or in an east Asian population.

[SOUND] [APPLAUSE]

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