In RA, Treating Heart Disease and Other Comorbidities

Stephen Paget, MD; Sergio Schwartzman, MD


November 30, 2016

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Editor's Note: This post originally appeared on the Hospital for Special Surgery's eAcademy.

Stephen Paget, MD: I'm Steve Paget, the physician-in-chief emeritus at the Hospital for Special Surgery in New York City. We're here today to discuss comorbidities in inflammatory joint diseases.

Sergio Schwartzman, MD: I'm Sergio Schwartzman, an associate professor here at the Hospital for Special Surgery.

Dr Paget: Sergio is quite expert in a few areas of inflammatory joint disease that I think are really important to discuss today. His knowledge spans the breadth of rheumatoid arthritis (RA), spondyloarthritis, psoriatic arthritis, ankylosing spondylitis, et cetera.

Maybe 15 or 20 years ago, I and other scientists here convened a group of investigators to try and decide whether atherosclerosis was premature in people with RA and lupus. We found that the risk for this is actually quite high. There seems to be a spillover effect of the proinflammatory cytokines on the endothelial cells to the point where, I believe, premature atherosclerosis is an extra-articular manifestation of the disease.

What are your thoughts about that, Sergio, and what to do about it?

Extra-articular Manifestation vs Comorbidity

Dr Schwartzman: The first question is what is an extra-articular manifestation of the disease, and what is the comorbidity. I'm not sure that they are exactly the same thing. When I think of comorbidities, I think of complications from the disease, whereas if I think about an extra-articular manifestation of the disease, it's almost like a different organ system has been targeted by the same disease process.

But your argument is a good one, because you're saying that the cardiovascular system, in RA as well as in psoriatic arthritis or spondyloarthritides, could be an independent organ system that is being targeted by the immune system. However, this could just be a spillover effect.

As I try to differentiate between the two, there's one common theme that arises: If you control the systemic disease process, you're very likely, although not always, to control either the comorbidity (if we want to term it that) or the extra-articular manifestations.

Cardiovascular Risks

Dr Paget: Let's talk a little bit about that. Which of the disease-modifying drugs that we use has actually been shown to decrease cardiovascular morbidity and mortality?

Dr Schwartzman: I think maybe first we should talk about the different diseases, because they're not exactly the same. If we think about RA and its comorbidities, cardiovascular disease heads the list. And as you've mentioned, we know that patients with RA are two to three times more likely to have a heart attack than patients who don't have RA. They're 30% more likely to have a stroke. They have a higher incidence of hypertension; that may be medicine-related, or it may be related to the disease process itself. Cardiovascular disease, in my mind, heads the list in terms of risk factors in RA that I would associate with comorbidities.

In psoriatic arthritis and ankylosing spondylitis, although cardiovascular disease is indeed important, it's actually within the spectrum of another comorbidity of that disease that we don't see in RA, which is metabolic syndrome. Patients with psoriatic disease are much more likely to have metabolic syndrome.

If we start the list of comorbidities with cardiovascular disease, in terms of therapies that we've used now to treat both of these diseases, it's been demonstrated that some of the biologics increase lipid profiles and total cholesterol. What's also been demonstrated is that some of the anti-tumor necrosis factor (TNF) medications actually may protect you from cardiovascular risk.

Potentially Overlooked Comorbidities

Dr Schwartzman: Cardiovascular risk has gained the most interest and the most emphasis, but if we go down the list of comorbidities in RA, osteoporosis and pulmonary disease are risks as well. That's something that we're seeing much more in RA.

The other worrisome comorbidity of RA is cancer. Untreated or poorly treated, active inflammatory RA is the greatest risk for cancer across the board.

Dr Paget: Which ones?

Dr Schwartzman: Lymphoma has gotten the most press, and perhaps that is driven by a very active immune system that's not controlled. But across the board, we've seen from the European studies in the largest databases that many cancers are likely to present in poorly controlled RA.

The ones that head my list of specific cancers are probably skin cancers, including melanoma, and probably one solid cancer, lung cancer, which may be slightly more expressed. But you see the same thing that you see in cardiovascular disease, which is that if you control RA, you're less likely to develop these.

Dr Paget: So for example, it's common that we use methotrexate as a disease-modifying drug, and patients will often say, "What about this lymphoma issue?" It's usually the thing that scares them most. I usually tell them that in actuality, RA itself has a 5- to 10-fold increased risk of developing lymphoma, which is increased further if you have Sjögren syndrome. It's my belief that more optimal control with methotrexate, for example, could very well decrease the risk. And yet, I'm not sure we're ever going to have that study.

Dr Schwartzman: I completely agree with you, but I have to remind you of a paper that you wrote some years ago[1] and that I was a coauthor on, which was one of the earlier papers on methotrexate's association with lymphoma.

Dr Paget: Let's talk about that for a second. We've had 50 rheumatologists working here for 50 years, and maybe we've seen one or two of these cases. One of them, just by stopping methotrexate, went away, and one needed chemotherapy. The important point there is that 50% of the lymphomas actually have Epstein-Barr virus in them. So there is this triad of disease, medication, and Epstein-Barr virus, and if you pull one part of the triad out, it may very well go away. It does exist, but it's reasonably uncommon.

Dr Schwartzman: I agree, and you can say the same thing for the anti-TNF agents, whose boxed warning includes lymphoma.

Dr Paget: Isn't that more in children, though?

Dr Schwartzman: Not necessarily. It's in adults and in children. There's a special lymphoma in kids who have inflammatory bowel disease and get treated with an anti-TNF and azathioprine or 6-mercaptopurine, which is hepatosplenic T-cell lymphoma.

The reason behind the warning label is that more lymphoma is seen in patients who are on anti-TNF agents. You have to remember that in early studies, patients who had the most active disease received the anti-TNF agents. I believe that in most patients who develop lymphoma and happen to be on anti-TNF agents, this is not necessarily due to the anti-TNF agents, but to active disease.

Having said that, there are published accounts of a very small number of patients who have just been treated with anti-TNF agents and in whom, when they develop lymphoma, stopping the anti-TNF agents (just like you mentioned in methotrexate) will result in the lymphoma regressing without any therapy.

Dr Paget: It would be like getting rid of Helicobacter pylori with Mott cell tumors of the stomach.

Dr Schwartzman: I think the analogy is the same. It's not that there are only two variables: disease activity and therapy. We've identified some viruses that are maybe implicated. What else are we not identifying that is implicated? What's the role of smoking, for example, in that cohort of patients? Is it so small that you can't differentiate it?

As I go down the list in RA, I think the understanding of some of the comorbidities and the co-manifestations of the disease has changed practice patterns over the past decade. When we started treating patients with RA, we weren't concerned about cardiovascular disease. That was for the internist or the cardiologist to deal with. What's begun to happen is that, given that these are our patients who are dying of an extra-articular manifestation of the disease, practice patterns are beginning to change.

I think we are now more likely to address lipids, whereas we didn't even check lipids 20 years ago. Every single one of my patients gets a lipid profile from when I first meet them. If they're not addressed by the internist or cardiologist, I address them.

Immunizations are another example. We have to be concerned about live vaccines in patients who are potentially going to receive biologics at some point. Is that a comorbidity of the disease, infections? I give the internists the chance to address the issue of immunizations, but if they don't, I do.

Treating the Disease, or the Patient?

Dr Paget: I wanted to address this concept of the principal caregiver. People's medical care is tremendously partitioned. They may have five different doctors generating their medication list, and each one should try to simplify their medicines.

Who in your mind is responsible for controlling hypertension, atherosclerosis, cholesterol, immunizations, diabetes, et cetera? You mentioned before that if you find that the internist doesn't do that, you take that upon yourself. What is your role in the care?

Dr Schwartzman: I think our role as physicians is to take the absolute best care of our patients that we can. You're right about the partitioning of care that has evolved in medicine over the past two decades. Seeing that evolve over time, I've been impressed with how fragmented care leads to poor patient outcomes in the end.

I think the pendulum is now swinging back. Every rheumatologist is an internist—we have to be to become rheumatologists. There are certain parts of internal medicine diseases, or what we're now calling "comorbidities," that affect our patients as much as the diseases do. A heart attack in your patient is worse than a Clinical Disease Activity Index (CDAI) score of 45—a very active disease.

So, am I taking care of a disease, or am I taking care of a person? Hopefully, I'm taking care of a person. Given that, the way that I've restructured myself over the past decade is that the comorbidities or extra-articular manifestations of the disease that directly affect my patient are the ones that I'm taking on personally, if the internist is does not or is not willing to do so.

Dr Paget: Are you trying to address both the quantity and the quality of their life?

Dr Schwartzman: The challenge that we have is time. If we really deal with every single issue that a primary care physician deals with (eg, thyroid disease, viral upper respiratory tract infections), I think that that's where we begin to [dilute] our power to control our time frame in terms of taking care of patients.

It's a delicate balance right now in terms of my practice. All of my patients, like yours, are free to communicate with me any time. They have our email addresses, and we know that they can call us about or email us about anything. In a sense, I am functioning as the primary care doctor, but my focus on rheumatology allows me to disseminate some of those responsibilities that I don't think are either immediately life- or health-threatening to the patient.

I don't know that the pendulum has swung completely back yet, but at least for me on this topic we're addressing today, the comorbidities we've already talked about are as critical in terms of the care of my patients as the disease process itself. If I were to ignore that, I think that I would be providing poor care.

Dr Paget: Let's go into one thing that you just mentioned, which I think is key: the modern use of technology. We try to optimize the care of our RA patients. In actuality, we may see them every 3 months, when there's lots going on in between. I tend to use email and text messaging to get a more current concept about how people are doing, because it's the area under the curve and gives you the global concept of what happens in that month. Although you may assess this during their visits, there's a lot going on in between that their organ systems and molecular components are seeing.

Dr Schwartzman: I have a very good role model, who's taught me how to do that very well. His name is Stephen Paget, so I do the exact same thing.

Communication with your patients is critical, and you have to use the most efficient form. Like you, every single one of my patients has my email, and they're free to contact me at any time, even when other rheumatologists are covering for me. That's an arena where technology has really provided great assistance in terms of patient care. It establishes a communication that the patient is very comfortable with and that I am very comfortable with, because as you said, it happens in the in-between period. Patients can tell me what's happening. They can ask, "Should I go to the Caribbean because I have RA and am on an anti-TNF agent, considering that the Zika virus and chikungunya are there?" That's not something the patient is going to come to the office and talk to you about, but it's something that is easily answered over email.

Underlying Genetic Components

Dr Paget: You mentioned metabolic syndrome, which in many ways characterizes more psoriatic arthritis, but probably all the spondyloarthropathies. Do you think that there's a genetic cassette that combines psoriatic arthritis, psoriasis, and metabolic syndrome, or do you think that the metabolic syndrome evolves relative to the underlying pathogenesis and the medicines we use?

Dr Schwartzman: One of the comorbidities that we haven't yet discussed at all, which is really applicable to both psoriatic disease and RA, is depression. However, it is more often manifested in patients with psoriatic disease—psoriasis and psoriatic arthritis.

Dr Paget: "The heartbreak of psoriasis."

Dr Schwartzman: Right. That may be one of the components that adds to the psoriatic patient having metabolic syndrome, because one of the responses to depression is eating and being overweight. Is there a genetic cassette for that? I'm sure there is. There are programmable mouse models where almost no matter what they eat, they're going to be obese or skinny. There's got to be a genetic component to that as well, which is becoming increasingly more complicated as we understand more about the microbiome. I think the metabolic syndrome is a very real part of psoriatic disease, whereas I think there are components of that in RA.

The question then becomes, how much does depression play into that? We don't really highlight depression in RA, but if you look at studies that address the issue of comorbidities, it is highlighted in psoriatic disease. Nonetheless, if you look at some of these large studies in patients with RA, such as the COMORA study from 17 European countries,[2] depression is indeed expressed in that group of patients. There are degrees in different countries, but I think that there is a cassette for metabolic syndrome.

I'm curious to see how much of that cassette is the microbiome. It's a different entity that we could probably talk about during another discussion. But, as I think about comorbidities, clearly metabolic syndrome stands out more in the psoriatic group.

Focus on the Microbiome

Dr Paget: I want to follow up on the microbiome, because it's an extraordinarily important concept. We are 109 cells and we contain 1010 cells of bacteria, most of which we don't know about. They don't culture out, and were instead discovered on a molecular level by the microbiome project at the National Institutes of Health (NIH).

There's the old concept of you are what you eat. Right now, almost every patient of mine who has RA or psoriatic arthritis has gone through the Internet and read things that say they shouldn't eat white foods; lactose-containing food; gluten-containing foods; nightshade vegetables, such as tomatoes; et cetera. You can't eat anything. I usually tell them if a specific type of food invariably leads to flares, they should avoid that. The fact is, I do have some RA patients who clearly flare when they eat certain things.

Given the concept of providing global principal care to your patients, what do you tell them on this topic? Do we give it over to the integrative care people?

Dr Schwartzman: They've already taken it. I think the microbiome is unbelievably complicated. It clearly has a role in disease—not only in rheumatic and immunologic diseases, but others, such as cardiovascular and malignant disease. We don't yet understand it, but we're learning more and more.

The NIH project is only one of many projects looking at the issue of the microbiome. The microbiome exists in many different parts of our body, such as our skin or gastrointestinal tract, but it's very different in these different areas.

There've been studies that have linked certain microbiomes with some of our diseases, the best known of which is probably Crohn disease. However, there are microbiome studies that have also been published in RA and in psoriatic arthritis. The challenge from a practical perspective is that although these have been noted in published studies, they've been in relatively small numbers of patients and there's no direct disease association. This is to say, changing from one microbiome to another has not yet been tested, and it's very difficult to do so.

By the age of 2 years, your microbiome is for the most part established. It's based on whether you're vaginally delivered or delivered by cesarean section, and whether you are breastfed or bottle-fed. Those have very dramatic impacts on the microbiome. After that, you can change a microbiome, but not by a lot. When you get a gastrointestinal illness and have diarrhea, your microbiome in your large bowel will change. But after that resolves, guess what comes back? Your microbiome.

Dr Paget: There's been some interesting work with regard to patients with refractory Clostridium difficile infection. Many of them are patients who are taking immunosuppression. They received fecal transplants, and it doesn't work all the time. It's a variable thing, and it's tough to know. It's not like giving an antibiotic to a bacteria that it's sensitive to.

Dr Schwartzman: The best model right now is, when patients ask you whether they should change their diet, you can say yes. Is that affecting the microbiome, or is there something chemically inherent?

Dr Paget: Celiac disease would be the best example of that, right?

Dr Schwartzman: Right.

Dr Paget: An autoimmune disease with a genetic predisposition. If you avoid certain food, all of the problems go away, including lymphoma and adenocarcinoma of the bowel down the road. It's quite amazing.

Dr Schwartzman: It is. With the microbiome, it's a little bit too early to advise patients. I do the same thing you do: If a patient tells me that a certain food precipitates flares, I tell them obviously to avoid it. But do I tell them to use a certain probiotic? There are some rheumatologists who do, but I don't, because I don't think that it's been well studied. Some work has shown that certain probiotics provide benefit, but I think we're way too early in terms of understanding that.

The issue is that different probiotics have different bacterial species in them. You don't know whether they're good or bad. You just know that somebody is calling them a probiotic, that's all.


Dr Paget: What I'm get from this conversation is that inflammatory joint disorders, whether they're clinically called "RA" or "spondyloarthritis" or "psoriatic arthritis," have an increased risk for cardiovascular and cerebrovascular disease as an intrinsic or associated component of the illness. Also, the optimal treatment recommended today probably does affect the outcome. Is that correct?

Dr Schwartzman: Absolutely correct. I think we can argue very strongly for that in terms of cardiovascular disease, and less strongly for the other comorbidities we've mentioned. When it comes to whether you can improve these comorbidities with better disease control, we don't have as good data with osteoporosis; in depression, the answer is "probably," but again the data are not very good; and with metabolic syndrome in psoriatic disease, there are some data that support controlling the disease makes metabolic syndrome better.

Intuitively, the idea that controlling a systemic disease process will control all of these extra-articular manifestations is very attractive to us. It's been demonstrated for cardiovascular disease. For all of these other comorbidities, I think you still have to do the research to prove that.

Dr Paget: From my reading, it's been shown in large population studies that methotrexate and anti-TNFs, when they control the disease optimally, decrease the risk for cardiovascular disease. Does triple therapy [do so]?

Dr Schwartzman: I don't know that I've seen that information in triple therapy.

Dr Paget: Would you expect that a CDAI score that's brought down from triple therapy, vs methotrexate plus an anti-TNF, is equal?

Dr Schwartzman: That's a tough question. Really, what you're asking, independent of comorbidities, is whether a biologic therapy with or without methotrexate, depending on the biologic we're using, is better than or the same as triple therapy. There have been studies that addressed that. The TEAR study[3] actually showed that they were very similar, although it was very underpowered. My answer is that it's difficult to maintain patients on three remittive medications at the same time.

My intuitive sense—particularly from the radiographic data, which are demonstrated in the TEAR study—is that the biologics are better than triple therapies. We don't use triple therapy very much here at the Hospital for Special Surgery. There are a couple of issues with it: One is the issue of compliance, and two is the issue of efficacy. There have been great debates about this across the board, depending on your bias. If you were to ask my opinion, I think I would lean very much more on biologics as opposed to triple therapy.

Dr Paget: So not all CDAI scores are created equal? A CDAI score of 1 that's generated by triple therapy vs a CDAI score of 1 that's generated by methotrexate and an anti-TNF—are they created equal?

Dr Schwartzman: I think they're created equal. The CDAI, the Disease Activity Score, the Simplified Disease Activity Index and—I'm reluctant to say this, but I have to, on the basis of the literature—the Routine Assessment of Patient Index Data have all been validated across radiographic outcomes and validated internally against each other. So what's the gold standard?

Dr Paget: Because this discussion is about comorbidities, what I'm getting at is that I understand treatment to target a certain CDAI score, and you may get there using triple therapy vs methotrexate plus an anti-TNF agent. But do you believe that that attainable CDAI score is equal with regard to the extra-articular manifestations?

Dr Schwartzman: In terms of the extra-articular manifestations, no. In terms of the disease process, yes. Why am I saying no for the extra-articular manifestations? I would say it depends on the extra-articular manifestation.

Let's look at extra-articular manifestations of disease by picking autoimmune eye disease as an example. For autoimmune eye disease, although triple therapy can work, as an extra-articular manifestation of spondyloarthritis in general, monoclonal anti-TNF agents are superior to remittive medications. In terms of the meaning of the CDAI, however you get to that target doesn't make a difference to me. Whether it's triple therapy or a biologic plus methotrexate, the CDAI is the CDAI, and that's going to predict ultimately the radiographic change and disability.

However, in terms of specific therapies, it depends on what extra-articular manifestation you're asking about. Does triple therapy surpass or equal biologic therapy in preventing cardiovascular disease in patients who have RA?

Dr Paget: It contains methotrexate, and we know what methotrexate does. But does the addition of two other medications, which are quite cumbersome from a treatment point of view, warrant it?

Dr Schwartzman: Exactly; that's the question.

Dr Paget: Thank you so much for joining us today. Sergio and I had a great time talking about a very important topic.

Dr Schwartzman: Thank you.