Anticitrullinated Protein Antibodies in RA-ILD

In this podcast, Dr Vanessa Kronzer talks about research she and her colleagues conducted into the association of anti-citrullinated protein antibodies with incident rheumatoid arthritis associated interstitial lung disease.

Vanessa Kronzer, MD, is an assistant professor of medicine and rheumatology fellow at Mayo Clinic in Rochester, Minnesota.

Reference: Kronzer VL, Hayashi K, Yoshida K, et al. Fine specificity protein antibodies and prediction of rheumatoid arthritis-associated interstitial lung disease. Lancet Rheumatology. Preprint posted online September 14, 2022. http://dx.doi.org/10.2139/ssrn.4217729

TRANSCRIPT:

RALN:

Welcome to this podcast from the Rheumatology & Arthritis Learning Network. I'm your moderator, RALN:. Today, I'm speaking with Dr. Vanessa Kronzer, a rheumatologist with the Mayo Clinic in Rochester, Minnesota, about research she and colleagues conducted into the association of anticitrullinated protein antibodies with incident rheumatoid arthritis associated interstitial lung disease. Thanks for joining us today, Dr. Kronzer.

Dr. Vanessa Kronzer:

Yeah, happy to be here. Thanks for having me.

RALN:

So to begin, could you please explain exactly what anticitrullinated protein antibodies and antinative protein antibodies are?

Dr. Vanessa Kronzer:

Yeah, I'm happy to. This was something that I needed to brush up on, too, when I was doing this study as well. So the short answer is there are two kinds of antibodies that anybody theoretically can have,  and recall that antibodies are those Y-shaped proteins in our immune system that help us fight infections and they react to other proteins.

And we're all estimated to have a quintillion of them, which means a million trillion of them. But these particular antibodies we studied, for whatever reason, seem to be more common in people with RA, and also it turns out RA-ILD. So that's what the protein antibodies parts means. So now, are you up for hearing the citrullinated part?

RALN:

Please do explain!

Dr. Vanessa Kronzer:

Yeah, we'll dive in. So citrullination is just the amino acid arginine changing into citrulline, which usually happens in areas of damage in our bodies. Native on the other hand means it's not citrullinated. Since our bodies have over 10,000 proteins, that means theoretically there could be hundreds of proteins that could be citrullinated.

Okay. So putting together what we discussed then, when our immune system makes antibodies that react against each of those specific citrullinated proteins, they're called anticitrullinated protein antibodies or fine specificity ACPA.

RALN:

And antinative protein antibodies are those that are not citrullinated?

Dr. Vanessa Kronzer:

Yeah. Against proteins that are not citrullinated. Yep.

RALN:

Great. How does all this relate to the development of interstitial lung disease among patients with rheumatoid arthritis?

Dr. Vanessa Kronzer:

Yeah, so if you are familiar with rheumatology, you might have heard of the clinical test called anti-CCP, or anticyclic citrullinated protein test, that's often used to help diagnose RA because two-thirds of patients with RA have it, whereas most people without RA don't.

And it increases the risk of RA-ILD 2, which we have known for many, many years. So how are the fine specificity ACPAs we studied different from that clinical CCP test we are all familiar with? Well, you can think of the CCP test as an umbrella test that encompasses a few fine specificity ACPAs, but remember I said there could be hundreds of them and a CCP test doesn't measure all of them, just a few.

And that's important for RA, because we know at least 10% of patients, RA patients, who are negative for CCP can be positive for other fine specificity ACPAs. And now we know from our study in RA-ILD that certain fine specificity ACPAs that are also not encompassed by the CCP test can indeed be associated with an increased risk of RA-ILD.

RALN:

So, tell us about your findings.

Dr. Vanessa Kronzer:

Yeah, so the study demographics, we had 84 RA-ILD cases and 233 matched RA, but no ILD controls. And the key findings, I would say there are 2, the first key finding was that 6 antibodies, fine specificity antibodies were strongly associated with RA-ILD—3 of them citrullinated, and 3 of them native, which was a surprise for us because we were expecting more of the citrullinated to be associated.

But regardless, these 6 antibodies predicted RA-ILD risk better than all the clinical factors for RA-ILD risk combined, and the area under the curve or AUC was very good at 0.84, whereas before in a study we had done of just clinical factors, it was only 0.73.

So since these antibodies were so predictive, we took the next step then of developing a risk score for RA-ILD for clinicians to use that combines these antibodies with the strongest clinical factors and it's very good with a specificity now greater than 93% for your RA patients to have RA-ILD.

RALN:

That's outstanding. It preempts my next question, which was how can the practicing rheumatologist test for these antibodies? Is this difficult? Is this expensive? But apparently you've created a tool that makes the process more …practical for the practicing rheumatologist?

Dr. Vanessa Kronzer:

Yeah. Yeah, because we just made this discovery, labs haven't quite caught up to measuring all these fine specificity ACPAs yet, but hopefully they will once they're aware of our findings. I know that our lab in particular, we're looking into expanding to fine specificity ACPAs right now as we speak.

But because we realize that right now, labs don't have these yet, we also made a score without the biomarkers so that clinicians can start screening their RA patients for RA-ILD right now, using a threshold we considered clinically important of 50% of the patients you screen would have RA-ILD.

We thought that's the cutoff used in scleroderma, for example, about half of patients with scleroderma have ILD and we screen all of them. So we established that as a cutoff score and then told people that if your patients have this score, you should consider screening for them.

RALN:

How can they obtain this scoring system?

Dr. Vanessa Kronzer:

It's in our paper, which is published in Lancet Rheumatology, and it's very quick to use, you just add up the points and there you have it, just like the myositis score.

RALN:

Okay. How common is ILD? I think you just said, about 50% of the patients with scleroderma have it, is it about the same rate with RA?

Dr. Vanessa Kronzer:

So it's a little bit less, which is why screening is not standard of care for all RA patients. But I think that as a result, we have made the mistake of not screening anybody with RA unless they have symptoms. And I think that what we should be doing falls in between, which is to screen the high-risk patients.

That's why we made the point of doing this study. In RA, about 1 in 6 individuals have RA-ILD and that's especially important because having RA-ILD increases their mortality by 2- to 10-fold, compared to patients having RA without RA-ILD.

RALN:

Have you seen any changes in the prevalence of ILD among RA patients?

Dr. Vanessa Kronzer:

So we recently did a study in the Rochester Epidemiology Project to see if incidence was changing over time and didn't see much of a difference.

RALN:

That's good news, at least. Your paper mentioned there's some other clinical factors that may also contribute to patients with rheumatoid arthritis developing ILD. Can you tell us a little about that?

Dr. Vanessa Kronzer:

Yeah, the clinical RA-ILD score that I've mentioned that we developed incorporates the top four clinical factors that we and others have previously found. And in order of their risk, the number 1 is smoking, especially more than 30 pack-years. Number 2 is high RA disease activity.

Number 3 is current glucocorticoid use. I think a lot of people weren't familiar with that before our study that we published a couple years ago, but it does seem that current steroid use may increase the risk of ILD. And then fourth is obesity.

RALN:

So, no real surprises there I would assume?

Dr. Vanessa Kronzer:

Yeah, so smoking and RA disease activity have been known to be risk factors for RA-ILD for some time. But our study that we published a couple years ago, like I mentioned, current steroid use was somewhat of a paradigm shift as well as obesity. That was a newer finding as well.

RALN:

So if the patients at the highest risk of developing ILD can be more easily identified, then what kind of steps could the practicing clinician take to help patients reduce their risks? And I think one of the answers clearly is going to be lifestyle changes.

Dr. Vanessa Kronzer:

Yeah. So the biggest takeaway, if our listeners take nothing else away from today, I want clinicians to know that we are currently not routinely screening RA patients for RA-ILD because we don't know who to screen. But now we do know how who to screen. So now I think we should be screening these patients, especially because of how common and deadly it is in our RA patients.

Hopefully this will even be incorporated into RA guidelines like it has been for scleroderma. And you make a good point though about the lifestyle changes for our high-risk patients who are lucky not to have developed RA-ILD yet, we should study that.

Like I mentioned, smoking and obesity might be ones that are modifiable. And for clinicians, keep in mind that reducing your patient's RA disease activity and consider not prescribing steroids might help them as well.

RALN:

So as with many autoimmune illnesses, keeping the disease under control seems to be essential to the overall health of the patient?

Dr. Vanessa Kronzer:

Mm-hmm. Definitely.

RALN:

Okay, well, thanks for taking the time to talk to us today about this. It's really interesting and I look forward to talking with you as your research continues.

Dr. Vanessa Kronzer:

Yeah, sounds good. Likewise, thank you.