Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune condition. While it typically results in a symmetrical and erosive arthritis, many patients with rheumatoid arthritis have an atypical presentation and up to 40% have extra-articular manifestations. RA tends to be progressive over years and can be quite debilitating. Fortunately, there are some new treatments available that have given patients hope of remission from this disease. In this podcast, we explore RA and discuss its clinical manifestations, how to establish a diagnosis and management considerations. Our guest is Vanessa L. Kronzer, M.D. , from Mayo Clinic Rheumatology.
Rheumatologic problems are some of the most common health conditions we see as primary care professionals. They can become frustrating for both the provider and the patient, as in many cases it may take months and sometimes even years to establish a correct diagnosis. There are a variety of new tests available to help us confirm a diagnosis, as well as multiple new and effective treatment options. This episode is part of a seven-episode miniseries on Mayo Clinic talks dedicated to rheumatologic health problems to aid in the recognition, diagnosis, and treatment of your patients. Please find these additional episodes where you listen to podcasts or on CE.mail.edu. This is Mayo Clinic Talks, a curated weekly podcast for physicians and healthcare providers. I'm your host, Darryl Chetka, a general internist at Mayo Clinic in Rochester, Minnesota. Rheumatoid arthritis is a chronic inflammatory disorder representing an autoimmune disease. While it often results in a symmetric, erosive, and deforming arthritis. Up to 40% of those with rheumatoid arthritis have extra-articular manifestations affecting multiple organs. It tends to be progressive over years and can be quite debilitating. Fortunately, there are some new treatments available which have given our patients hope of a remission from this disease. Today's podcast will explore rheumatoid arthritis and we'll discuss its clinical manifestations, how to establish a diagnosis and its management. Our guest is Doctor Vanessa Kronzer from the division of Rheumatology at the Mayo Clinic. You're listening to Mayo Clinic Talks. Vanessa, welcome and thank you for joining me today. Thank you so much for having me, Doctor Chaka. Good to be here. Well, let's start by talking about risk factors for rheumatoid arthritis. Are there some individuals who are maybe more likely to get this than others? Yes, I'm so glad you asked this question. Epidemiology is a topic near and dear to my heart. And the answer to that is there are more women than men who get rheumatoid arthritis, about 2 or 3 to 1. And it's also bimodal with peaks in the 30s as well as age 50s to 60s, although it can occur at any age. There are also genetic risk factors, which is an area that I study as well, specifically the HLA region. And it's about 30% heritable rheumatoid arthritis is. After that, there are a couple of risk factors that everybody should know about. The most important one that we've known for decades is smoking. Smoking strongly increases the risk of rheumatoid arthritis around threefold, and it depends on how much people smoke. The more they smoke, the higher the risk. But what people may not be as aware of after smoking is that we're now realizing obesity also contributes to increased risk of RA as well. There was a recent study suggesting that smoking and obesity each contribute around equal portions to the onset of rheumatoid arthritis now at this point in time. And then respiratory tract diseases might also increase the risk of RA which is an area that I study. OK. Well, rheumatoid arthritis is one of the more common rheumatologic conditions and as a general internist, you know, if we've been in practice even a few years, we've typically seen patients with this. So let's go over the typical presentation of RA. Yeah, the typical, as you nicely mentioned at the beginning, it's usually symmetric, especially in what we call the MTPs, which are those little joints that connect the fingers to the hands, as well as the wrists and the MTPs, which is where the toes connect to the foot. Those are the most classic spots for rheumatoid arthritis. How often is it atypical? Cause I've had a few patients who've presented in an unusual manner, and then maybe a few years later, it's been diagnosed as RA. Yeah, I would say almost every case of RA is atypical in some way. Whether it be that it, men, which I mentioned is less common, or young age, it may not be in 30s, maybe it's in the teens or the 20s or old age. I've seen even patients up to the age 90, in their 90s, diagnosed with RA or maybe no family history. In fact, that's pretty common, even though family history does increase the risk. Most people, because it's rare, don't have a family history of RA or autoimmune disease. And then the other thing that even Theologists sometimes forget about is that RA can present in a palindromic way. It's called palindromic rheumatism, where it comes on in kind of bursts of joint pain that go away, almost kind of like gout attacks, where it comes and it goes and it comes and it goes. It may not be a chronic gradual onset, which is the typical presentation. So, as a mentor of mine once said, some patients just don't read the textbook. Yes. Yeah, everybody is individual. Yeah. Well, I think one of the biggest difficulties we sometimes have is differentiating rheumatoid arthritis from osteoarthritis. How might the two contrast? This is a key point that we teach right away when people come to rheumatology clinic for a residency or fellowship. And the key point here is that rheumatoid arthritis is inflammatory, meaning we look for morning stiffness lasting longer than 30 minutes typically, and that the joint pain gets better with activity and worse with rest. This is in contrast to osteoarthritis, where the morning stiffness is usually less than 30 minutes. It gets worse with activity and better with rest. And the presentation in the hands, which is a common area, has to be a bit more proximal than osteoarthritis. Yes, great point. So the distribution is also different. RA loves those MCPs, wrists and MTPs, whereas osteoarthritis loves the distal interphalangeal joints, the DIPs we call them. which give the little bony prominences at the ends of the fingertips. That is a spot that RA doesn't usually affect. And one other point I wanted to make on the topic of differentiating it is that I mentioned RA is inflammatory. Another common thing that we tell residents and other learners who come to rheumatology clinic is, remember, what is the most common cause of inflammatory arthritis? Because most people think that it's rheumatoid arthritis, but actually it's not. I pin people on this all the time. The most common cause of inflammatory arthritis is crystal disease, like gout and pseudo gout, also called CPPD. So it's important to think about distinguishing it from gout too. I've had a few patients where it's taken a while to establish a diagnosis of rheumatoid arthritis, and sometimes we have to tell the patients it hasn't quite declared itself yet. How often does that happen? This is a topic that has come to my mind recently because I've been doing chart reviews for a study we're doing of 3000 potential RA cases. And so I've gotten to see how the RA started in all of these cases. And it shocked me how often the RA did not start in a classic or typical RA way, and patients were often misdiagnosed or the physicians, even the rheumatologists were unsure at first, often. For some period of time. So I've learned from doing this that classic is very unusual and it's very difficult even for rheumatologists. And I know this frustrates patients because they want a diagnosis and just, you can't tell, is this gonna be RA? Is it gonna be Sjogren's, and it takes time. It does. Well, how does this disease tend to progress over time? Is it a gradual progression? Are there episodic flares? Historically, before we had the good treatments that you mentioned, it used to usually progress and flare over time, unfortunately. That was the historical way or thing that would happen to rheumatoid arthritis patients. But with good treatment that we can give upfront now, that has become much less common. And even into the early 2000s, now there's a 60% chance of long-term remission. Patients. In comparison, psoriatic arthritis is 90%, so it's less than psoriatic arthritis. But I think it's become even better now as we have more and more treatments. So there is a good chance of remission and not having those progressions or flares. So I think the key point that I want everybody to know about rheumatoid arthritis here is that early diagnosis and treatment is critical. And that's because the earlier patients are treated, the better the RA will be. There's this so-called window of opportunity that has been discovered of around 4 months, where if patients are treated within 4 months of symptoms, their chance of eventually going off treatment is much higher than if it's first treated later. So, if you're not sure, please send them over because time is important. Sure. Well, I think for most patients, The major life-altering symptoms are the joint pains, but with rheumatoid arthritis, you can get some non-articular complications as well. Can you, can you review those? Yeah. So one important one is RAILD Institial lung disease, that happens in 10 to 20% of people, and that's a common reason for mortality, especially in people who have untreated or active rheumatoid arthritis. So you would be watching for cough or shortness of breath that you can't explain in your patients with rheumatoid arthritis. There's also increased risk of heart disease and lymphoma as there is with any inflammatory condition, rheumatoid arthritis, Crohn's, or anything like that. And that's proportional to how active the disease is. So if it's well-controlled, then the risk of that is much lower, if not normal. OK. Is there any evidence that if you have rheumatoid arthritis, your life expectancy is shortened? So, again, that depends on how well the patients are treated. If they have persistent high active disease, mortality is 3 times higher than those who don't have rheumatoid arthritis, which is a 10 years shorter life expectancy, but if they're in remission or low disease activity, there There's no change in life expectancy. So I think that is a message of hope that we can give our RA patients now too. The point being though, early treatment is critical. OK. So, we have a patient who comes into our office and complains of arthritis. Um, what important questions should we ask them if we suspect rheumatoid arthritis is the cause of their symptoms? Yeah, I find myself asking the same three questions when I'm evaluating anyone who were suspecting RA. The first being what joints, looking for the distribution of the symmetric distribution, the MCPs, the MTPs, the wrists, etc. Second question is, what makes it better and what makes it worse? And if they don't specifically say this, I will ask about activity. How about activity? Does that make it better or worse? And then the third question I often ask is, what time of day is your pain the worst? I'm looking for them saying that it's in the morning time, and if they do say that, I'll say, how long does it take to get as good as it will get for the day, acknowledging that the pain never goes away, it just gets better or worse. So those are my top 3 questions. OK. What about physical exam? What are the classic findings we might see on uh examination? So, we look for synovitis, which is our rheumatology word for squishiness or bogginess or inflammation in the joint. And the ones we target are the same ones that were most common in rheumatoid arthritis. So the MCPs in the hands, the PIPs, the wrists, elbows, knees, ankles, and MTPs. Those are the ones where we especially zone in on. And how about laboratory tests? We often use these to help establish a diagnosis. Which ones are useful? Everybody knows to look for a rheumatoid factor and a CCP. Those are really good and important tests for rheumatoid arthritis, along with inflammation markers, the ESR and the CRP. So those are probably the top 4. But also, labs can be very helpful to rule out Mimics. So, I mentioned the most common cause of inflammatory arthritis is not RA, it's gout. So consider checking a uric acid if a patient might possibly have gout. Or as you mentioned, lupus is another mimic. So considering an ANA, I would say the second most common mimic though is psoriatic arthritis, for which we will often check an HLAB27 test. Another test though, that can be helpful is actually aspirating the joint that's affected, if it has enough fluid in it that you can get fluid out. That is extremely helpful because the cell count can tell you whether the patient's swelling is inflammatory or non-inflammatory, with greater than 2000 cells being inflammatory. And then you can also check for gout and pseudo gout by sending for crystals. So that's an extremely useful test that we do a lot. Well, rheumatologists certainly have an alphabet soup of laboratory. Uh, rheumatoid factor has been around for a long, long time. What exactly is it? Remember, antibodies are Y-shaped proteins that react to other proteins in our immune system to help us fight infections. And when the protein it reacts to is the stem of another antibody, that's called a rheumatoid factor. So, in other words, it's an antibody to an antibody. And the rheumatoid factor is we consider to be pretty non-specific, so we really don't get too excited. about them in rheumatology, especially if they're low positive or in older individuals where up to 20% of the normal population can have a positive rheumatoid factor, just like an ANA. So in addition to low tier false positive rheumatoid factors, aren't there other health conditions that can be associated with the rheumatoid factor? Other autoimmune diseases like Sjogren's, lupus. primary biliary cholangitis, but infections too. Hepatitis, HIV, malaria, or even just other infections that people are hospitalized with, and then cancer too. So, as I mentioned, it's pretty non-specific. OK. And there are patients who have rheumatoid arthritis but are rheumatoid factor negative. How does their disease differ? Yeah. So if a patient is negative for rheumatoid factor and negative for CCP, cause the CCP test is really the better one that we give more credit to. So if they're negative for both of those, we call them serro negative rheumatoid arthritis. And with those patients, I'm always wondering, OK, so what is it really? Is it something else like psoriatic arthritis? Is it lupus? Is it pseudogout? Is it gout? I'm always looking for symptoms that might suggest they have one of these diseases even over time because over time they might develop the symptoms that point us in one of those directions. If though, they continue to be sero negative rheumatoid arthritis, which 30% of patients with RAR, we can give patients The good news that it tends to be less aggressive, and we can more easily or more willingly try coming off of treatment because those patients tend to be less likely to flare off of treatment. OK. Well, X-rays can often be helpful in establishing a diagnosis of rheumatoid arthritis. What are the classic findings and which joints are best to X-ray? So, we like to get X-rays of the hands and the feet, and that's because the most common places to develop erosions are the MCP joints in the hands and the MTP joints in the feet. And what we're looking for are marginal erosions, which means erosions at the corners in those joints. The wrist too, by the way, can have classic erosions as well. And we get these at baseline because they can be present early in disease, even if the patient hasn't had symptoms very long. And that's another thing that's different than osteoarthritis, have those erosions. Yeah, yeah. Are there any other imaging studies that are useful other than just plain film X-rays? Yeah, these days, if we are not sure, even after our clinical history and exam, sometimes we will get an MRI of the most affected area. Oftentimes the hands is where people are most affected. So we can get a hand MRI when we're not sure, which is a very sensitive test. It can pick up erosions that aren't even present on X-ray yet. I wouldn't say any other imaging tests are standard. Sometimes people have done ultrasounds or joint scans, but we don't really consider those to be standard tests. OK. What's needed to establish a diagnosis of rheumatoid arthritis? Mhm. It's a clinical diagnosis still, and that's true of all rheumatic diseases is clinical diagnosis from a rheumatologist. That being said, classification criteria, which are used for research, are still extremely useful, especially for non-rheumatologists. So if you Google Rheumatoid arthritis criteria, and go to the images tab. All the first hits pull up your RA classification criteria. And what you'll see on that list are you get points based on having things that are classic for RA. So, small joint involvement, like the hands and the feet, rheumatoid factor or CCP being positive, ESR CRP being elevated, and grade. than 6 weeks are the most important factors when people did studies of what was most helpful. But patients don't always read the textbooks like you said, and ultimately, the way that we diagnose this is a clinical diagnosis in our clinic. So as with many conditions, it's a combination of history, physical exam, and laboratory tests, including imaging. Yes. All right. Well, let's get into the exciting part now. Let's talk about management. For years, we had very little to offer these patients, and now there's quite a few excellent opportunities for treatment that uh often results in remission. Can you review the treatment options that are available? Still, even after 40 to 50 years, the cornerstone of RA treatment is still methotrexate. And that's because it's extremely effective, well tolerated, low side effects, and so it's an oldie but goodie, I guess, and we still use it. Nothing has individually been able to beat methotrexate alone, so we do still use that first in patients when they're treated. However, 70% of patients don't respond to just methotrexate alone, and that's where these newer treatments have a very important role. A lot of biologics have been coming out that are extremely useful for rheumatoid arthritis, and we try one basically until one works. And luckily, we have so many these days that eventually we'll find something that works. What are the newer options out there? The next thing we do after methotrexate is usually a TNF inhibitor. Those aren't as new, but if patients don't respond to TNF inhibitors, that's when we start to get into some of the newer ones. TAC inhibitors are probably the next most effective drug. RA aftermethotrexate. So that's things like Zaljas, and those are great cause it's pills. There are some FDA black box warnings on potential side effects though, that are making us hesitant to prescribe these first. So it's more of a backup if some of the other treatments don't work. There's other treatments too like IL-6 inhibitors, Abatase, Toslizumab, or Actemra, which is used for COVID treatment too. We have lots of options. Mhm. So with all the different options you have available, can you achieve pretty close to remission in most patients with RA now? Yeah, I haven't seen more recent data. The most recent study I saw showed 60%, but that used data from the early 2000s. And this was before a lot of these biologics existed. So I do think from my clinical gestalt that our rates of remission are much better now. We just don't have the long-term follow-up studies yet to say what it is, but it does seem like most patients are able to get into remission now. OK. And I recall the term burnt out rheumatoid arthritis where at some point it just seems to no longer be inflammatory. Does that happen very often? Yeah. And those are the patients we're often not seeing back because they have the good fortune of it goes away and then they follow in the primary care clinic instead. There have been studies to see how often does this happen. And it seems that about 10% of patients diagnosed with rheumatoid arthritis achieve uh DMARD free remission, which means disease modifying. Drug free, so they're able to come off of their RA drugs and be in sustained remission. It might even be higher, especially if they're treated in that early 4 month window, it might even be higher than that. Mhm. OK. Well, Vanessa, you've given some really important information on rheumatoid arthritis. Can you summarize our discussion maybe with 2 or 3 key points? Yeah. I'll, I'll give you 3, Doctor Chetka. Uh, yeah. The first one, think about rheumatoid arthritis when a patient has inflammatory arthritis. And remember the definition of that is morning stiffness lasting longer than 30 minutes, better with activity, worse with rest, especially if it's in the RA classic joints like the MCPs, wrists, and MTPs. So that's 01. The second key point is, think about RA and refer early to us, and that's so important because the earlier RA is treated, the easier it is to treat, the higher the chances of remission, and the fewer complications they get long term. And then the third key point is, remember, RA is not the most common cause of inflammatory arthritis. The most common cause is crystal disease like gout and pseudo gout. So consider sending a uric acid or performing a joint aspiration to help sort that out. Right. We've been discussing rheumatoid arthritis with rheumatologist Doctor Vanessa Kronzer from the division of Rheumatology at the Mayo Clinic. Doctor Kronzer, thank you so much for sharing your knowledge with us today. Thank you, Doctor Chakka, it was a pleasure. 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