By Andrew Wang, MD, PhD, as told to Keri Wiginton

We have a ton of treatments for rheumatoid arthritis (RA). But with any given drug, we’re only helping a subset of people. I think one reason for this is because we don’t know how to match what kind of RA you have with what drug will work best.

When we answer both those questions, I think treatment will be vastly superior to what it is now.

How is RA treated today?

We already have a therapy that’ll help 100% of people. That’s corticosteroids, or prednisone. But what we’ve learned over the last 20 years is that the cost of steroids in the long term actually raises the risk of the very thing we’re trying to prevent, which is serious health problems.

For ongoing RA treatment, there’s a normal order of medication we’ll go through. You’ll try each therapy for about 3 months, switching from one to the other until we find what works.

Generally speaking, you start on methotrexate. That’s a disease-modifying antirheumatic drug, or DMARD. You may also take a TNF blocker, which is a drug known as a biologic. You may need to try more than one kind.

If you don’t respond to any TNF blockers, you can switch to a number of other biologics or DMARDs. We’re very fortunate to have so many choices.

Why do you need to treat RA?

There’s a common misconception that RA is only a disease of the joints. In fact, it’s a systemic autoimmune disease that affects many other organs. The most common just happens to be the joints.

Another important thing to realize is the main cause of death with RA and arthritis has nothing to do with the joints and everything to do with the increased risk of cardiovascular disease.

The reason that rheumatologists aggressively treat RA is, of course, to help with pain, disability, and other health problems related to the joints, but also to control inflammation which we think, in the end, drives heart attack and stroke.

That’s an important piece of information to have. You may not want to take your medication or stop smoking because you think: It’s just my joints. I can deal with it. But it’s actually not just your joints. Unmanaged RA raises your odds of other health conditions.

Why is RA hard sometimes hard to treat?

RA is kind of an umbrella diagnosis -- it’s probably a collection of a lot of different diseases. It shows in different ways. For example, someone may have mild or severe joint inflammation, mild or severe lung disease, or inflammation of the blood vessels. It’s not just about how well the drug works. You have to consider how treatment affects the whole body.

We can’t give someone a blood test to know how they’ll respond to a drug. That can be extraordinarily frustrating.

Roadblocks to the right RA treatment

In order to pinpoint the best drug therapy from the start, we need to know more specifics about RA. It is now becoming clear that every patient's RA is not exactly the same disease, which in part explains why different patients with RA often do not respond to the same therapy.

What are the specific similarities and differences between these different diseases (endotypes) that we refer to generally as RA? How do we identify and define those? Which endotype will respond to which treatment?

We’ve done this for some kinds of cancer and other diseases. For example, if you have an EGFR mutation in lung cancer, we have a good sense that you’ll respond to an EGFR therapy.

But with RA, there are two things that are less straightforward than cancer. It’s a polygenic disease, meaning there are a lot of small changes in a lot of different genes that, when they add up, tip the threshold for developing the disease.

The second thing is we don’t biopsy tissue in people with RA. Though there are exceptions, like if something is impacting the lung or kidneys and we need to rule out cancer or an infection.

Treatment down the road

It’s not just about how well the drug works. You have to consider how treatment affects the whole body. For example, there are really effective drugs to treat cancer, but they come with significant toxicity. I think the key is to develop RA drugs that will be potent but don’t cause that kind of harm.

We also want to know what aspects of life someone can control, other than taking medications, that will help in their disease process. There’s plenty of word-of-mouth evidence that lifestyle changes can ease symptoms. But it’d be good to get a handle on which ones will help which person the most.

Researchers are actively trying to figure all that out.

And the field is trying to identify the disease earlier. It’s very clear that folks prone to RA -- either because of their genes, family history, or environment -- have a kind of pre-disease phase, where there’s a detectable change in their immune system years before they have any inflammatory arthritis symptoms.

Then something happens and they transition into disease. In the future, scientists hope to find these initiating events. That may help us know who to target and when to suggest lifestyle changes or drug therapies.

But right now, we don’t really know any of that. And it’s impractical, and perhaps unethical, to screen everybody for RA.

Where is research headed?

Genetics drives RA only about 30% of the time. What’s causing the rest of it?

The emerging model in the field is that this is a mucosal disease, so it starts in the mouth, gut, the barrier tissues that separate us from the microbes that live in us or that we come into frequent contact with. Like the kind on our skin, for example.

The thinking is that maybe this mucosal and immune interaction explains why smoking, diet, and other factors greatly boost the odds someone will develop RA.

I’m hopeful about continued research into the microbiota and renewed interest in clinical phenotyping -- figuring out how the disease is different in each person. And if funding stays good, I think 10 years is a very reasonable time for us to learn more and translate that to new kinds of RA treatment.

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SOURCE:

Andrew Wang, MD, PhD, assistant professor, Yale School of Medicine.