CAR-T for Autoimmune Disease; Methods of Illegal Opioid Overdose

TTHealthWatch is a weekly podcast from Texas Tech. In it, Elizabeth Tracey, director of electronic media for Johns Hopkins Medicine in Baltimore, and Rick Lange, MD, president of the Texas Tech University Health Sciences Center in El Paso, look at the top medical stories of the week.

This week’s topics include a longitudinal study of Alzheimer’s markers, chimeric antigen receptor (CAR) T cells for autoimmunity, methods of illegal opioid overdose, and safety and efficacy of telemedicine abortion.

Program notes:

0:35 Method of use in drug overdose deaths in 2022

1:35 Smoking most common

2:30 Smoking, snorting, injection, and ingestion

3:20 Effectiveness and safety of telemedicine abortion

4:20. 99.8% NOT followed by an adverse event

5:20 Multiple groups benefit

6:20 Women who experience unintended pregnancy

7:00 New therapy for autoimmune diseases

8:00 How expensive are they?

8:36 Biomarkers previous to Alzheimer’s

9:36 Tau and total tau

10:36 Very long follow-up

11:36 Back up treatment very early on

12:41 End

Transcript:

Elizabeth: Predicting Alzheimer’s with a number of markers.

Rick: Routes of drug use in people that die of a drug overdose.

Elizabeth: The safety of telemedicine abortion.

Rick: And a new therapy for autoimmune diseases.

Elizabeth: That’s what we’re talking about this week on TT HealthWatch, your weekly look at the medical headlines from Texas Tech University Health Sciences Center in El Paso. I’m Elizabeth Tracey, a Baltimore-based medical journalist.

Rick: And I’m Rick Lange, president of Texas Tech University Health Sciences Center in El Paso, where I’m also Dean of the Paul L. Foster School of Medicine.

Elizabeth: Rick, why don’t you pick your choice?

Rick: This is a recent report in Morbidity and Mortality Weekly Report. It’s entitled “Routes of Drug Use Among Drug Overdose Deaths, 2020-2022”. It is a sad state of affairs to report that there have been more than 109,000 drug overdoses in the U.S. in 2022. Nearly 70% of those involved synthetic opioids other than methadone. Primarily we’re talking about fentanyl and fentanyl-laced drugs or analogs. The drug ingestion route for fentanyl and those causing drug overdose changed substantially.

What they determined in these almost 110,000 drug overdose deaths is the ones due to injection decreased by about 30%, whereas the percentage with evidence of smoking increased almost 75%. Now smoking, not injection, is the most commonly documented route of use in overdose deaths with, again, fentanyl and fentanyl analogs being the most common drug used.

Elizabeth: I was able to interview yesterday one of my colleagues at Hopkins, who is a substance use disorder expert, on this very data. He educated me because he said, “We shouldn’t just say smoking” — because some of it sure enough is heating it and then inhaling the vapors — but there is also a significant amount of what amounts to snorting it that is also taking place and that’s contributing to this.

He said there is a wide-circulating myth on the street that somehow that this method of administration results in fewer overdoses than injecting it. He said that’s a myth that we have to dispel. A respiratory failure is a respiratory failure, and you’re still at risk for that regardless of your method of administration.

Rick: Elizabeth, I’m glad you brought that up because I want to highlight that point. But before I do, these investigators looked at four different ways of drug ingestion. They looked at smoking that you mentioned. They also looked at snorting that you mentioned. They looked at injection and then also ingestion. Among those, the one that took off is smoking.

There is a perception there’s a reduced risk of overdose if you’re smoking, and that’s not the case. There is also the misperception that you can regulate the amount of drug that you’re ingesting. It’s cheaper; that’s why there are more people smoking than injecting it.

Elizabeth: Right. You mentioned something that he also reiterated yesterday, this notion that those who smoke it or snort it or use methods other than injection. These drugs are so cheap, Rick. It’s unbelievable — a dose for a buck. If you have to ingest it more often or smoke it or inhale it, so what? It only costs a dollar. That’s also a part of the calculus that has led to this massive increase.

Rick: Yeah.

Elizabeth: Let’s turn now to Nature Medicine. This is the “Effectiveness and safety of telehealth medication abortion in the United States.” This is the California Home Abortion by Telehealth (CHAT) prospective study that follows pregnant people who obtain medication abortion via telehealth from three virtual clinics operating in 20 states and DC between April 2021 and January 2022. These people were screened using a standardized no-test protocol that primarily relies on their medical history.

They looked at effectiveness, defined as complete abortion after the administration of 200 mg of mifepristone and 1,600 µg of misoprostol or lower without additional intervention. Among 6,034 abortions, just shy of 98% were complete without subsequent known intervention or ongoing pregnancy after the initial treatment. Overall, 99.8% of them were not followed by serious adverse events.

In total, 0.25% of patients experienced a serious abortion-related adverse event; 1.3% of abortions were followed by emergency department visits. They compared this with previous data that’s out there. It compares favorably and they basically say it’s safe and it’s effective.

Rick: What this study shows is in fact it can be done. It doesn’t increase the risk to the mother. Elizabeth, talk about circumstances where this might be in the best interest of the mother, or in other circumstances.

Elizabeth: That’s a soft toss, so thank you for that one. Clearly, as abortion is being restricted in many more states in the United States, it benefits women who are in places where it’s restricted and also women who are in rural areas or where significant travel is required, regardless of whether their state has restrictions on abortion or not. Younger populations and those who want to preserve their anonymity also benefit by the provision of this service by telehealth.

I was introduced to something very new to me here, which was synchronous versus asynchronous intervention with the clinic. What they meant when they used this terminology was that either you had a telehealth visit with the provider or they did it via text message. Sure enough, they found that the asynchronous, or text message, intervention was every bit as efficacious as the one that involved a face-to-face, or a synchronous, intervention. It just sounds like, “Yep, we can reduce barriers for women who are seeking abortion with this strategy.”

Rick: Yeah. Things about this study that are different than other studies: it was a no-test situation; they looked at synchronous versus asynchronous. This lines up with previous studies.

Elizabeth: Right. Finally, let me just note that their follow-up rate was 74%, and this is similar or higher than other studies that have looked at this kind of population. That is of concern to me, because I feel that women who experience an unintended pregnancy also need to be offered family planning services so they can avoid these kinds of circumstances in the future. If the follow-up is not robust, then that’s going to create circumstances where this could happen again.

Rick: Yeah. As these services become more stretched or unavailable for the reasons you have mentioned — rural conditions or the fact that the states that allow abortion are overwhelmed by requests from mothers in different states — this information, knowing that this is not an unsafe practice for the mother, is incredibly important.

Elizabeth: Let’s move on, then, to the New England Journal.

Rick: I teed this up as a new therapy for autoimmune disease, diseases in which the body attacks itself. The unifying feature of all of these is that something has sensitized the body to proteins that are in different organs. Our immune system attacks these organs. They are typically treated oftentimes with steroids or drugs that try to deplete the cells that make the immunoglobulin. These are called B-cells.

What these investigators did in 15 [people] that had autoimmune disease is they applied CAR-T therapy. We take out their T cells, we genetically treat them, and they gave them a single dose of CAR-T therapy. They followed these individuals for 2 years. In all individuals, they had a response that lasted for 2 years. Immunotherapy was completely stopped in all of the patients and the patients had no severe side effects.

Elizabeth: CAR-Ts, of course, very interesting. There are a number of other strategies that are similar that are significantly less expensive. That, of course, is the question with regard to employing this more widely in autoimmune disease, in addition to cancer.

Rick: This is the first time we’ve had a single-dose therapy that’s been effective in curing an autoimmune disease. Now, Elizabeth, you’re right. It’s expensive. How expensive is it? Well, in the neighborhood of about a half million dollars. Like all new therapies, it will get less expensive. It gives us some additional insights into the mechanisms to allow us to develop new therapies and to develop less expensive therapies.

Elizabeth: Plus, I think there are going to be modifications even to the CAR-T strategy just by itself.

Rick: Yeah.

Elizabeth: Remaining in the New England Journal of Medicine, “Biomarker Changes During 20 Years Preceding Alzheimer’s Disease.” This is really rather remarkable, I thought. This is a study that took place in China and I’m going to respectfully suggest it is probably the only place, or one of the only places, where it could have taken place.

They enrolled a bunch of people in the China Cognition and Aging study from January 2000 through December 2020. They had testing of cerebrospinal fluid (CSF), so they had to undergo lumbar puncture as a part of this, cognitive assessments, and brain imaging at 2-to-3-year intervals. A total of 648 participants in whom Alzheimer’s disease developed were then matched with 648 participants who had normal cognition.

Then they looked at the trajectory of the CSF biochemical marker concentrations, cognitive testing, and imaging in the two groups. They looked at what I’m going to call the usual suspects when it comes to looking at Alzheimer’s disease: amyloid beta — two different types of amyloid beta, 42 (Aβ42) and 40, for the cognoscenti among us — phosphorylated tau, total tau, neurofilament light chain, hippocampal volume, and cognitive decline.

What they found was that they could discern a difference in these trajectories first in the Aβ42 18 years previous to diagnosis of Alzheimer’s disease, the ratio at 14 years previous to diagnosis, [phosphorylated] tau 11 years, total tau at 10, neurofilament light chain at 9, hippocampal volume at 8, and cognitive decline 6 years previous to the final diagnosis.

Also, really tantalizingly, they noted that these changes in the CSF biomarker levels in the Alzheimer’s disease group initially accelerated and then slowed as the disease became manifest. God bless these Chinese participants for becoming a part of this study and enabling this rather invasive kind of testing to take place with them over this very long period of time.

The authors themselves note that one of the major limitations is that all these folks were of Han Chinese ancestry. Does that extrapolate to all of the rest of us who don’t enjoy that lineage? That’s a good question. We’re certainly coming up with a lot more markers that predict Alzheimer’s disease that are accessible in the blood. I’m wondering about the long-term efficacy of looking at these markers.

Rick: Elizabeth, as you said, this is a real tour de force study. You mentioned the fact that it is in just a single population. If you compare this study to what’s been looked at in people that have a familial history of Alzheimer’s, you see very similar changes over about the same time course. Here is where I think the rubber meets the road. By the time we start treating Alzheimer’s, it’s been going on for 14, 15, 16 years already. It should be no surprise that what we’re treating at that point — the cow is out of the barn and we may not be as effective. What we may need to do is back our treatment very early on.

Elizabeth: Exactly. This is also going to be dependent upon having an effective treatment for whatever the exact dysfunction is that’s going on at that point. I’m going to pose a question to you. If I said to you, “Hey, Dr. Lange. I’ve got a way of discerning if you’re at risk for developing Alzheimer’s disease. I need to do a lumbar puncture and I’m going to do PET scanning on you to look for all of these different things. Then maybe I have a treatment that might be helpful.” What would you say to that?

Rick: I personally would say I think it’s worth looking at. Here is where I think it’s going to be difficult. Let’s say you and I decide we’re going to do this randomized trial. We need to do it as soon as we detect these changes, but the manifestations don’t occur until 18 years later. We’re talking about doing a randomized double-blind study that lasts for decades. This is not going to be an easy problem to solve.

Elizabeth: On that note then, that’s a look at this week’s medical headlines from Texas Tech. I’m Elizabeth Tracey.

Rick: And I’m Rick Lange. Y’all listen up and make healthy choices.