Mortality in Rheumatoid Arthritis: A Story of Decline, Delay, or Plateau? Dr. Elena Myasoedova Save

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So during the next twenty, twenty five minutes we'll go over the underpinnings of mortality in rheumatoid arthritis, causes for mortality, as well as trends in mortality in rheumatoid arthritis over the past few decades, and we'll discuss the implications for clinical practice. All of us in this audience are united by one same process called aging. No one can deny that. Age is one major factor, risk factor for mortality and accumulation of morbidities, and rheumatoid arthritis is not an exception from that rule. In fact, majority of the risk of rheumatoid arthritis is attributable to, or happens the second half of life, and specifically after age 50.

Before age 50, the lifetime risk of rheumatoid arthritis is less than one percent. And why is that? That's because of the aging immune system, at least in part, that creates the loss of self tolerance and pro inflammatory milieu autoimmunity that results in this chronic lifelong disease that's called rheumatoid arthritis. In people who develop rheumatoid arthritis before the age of 50, there is a signature of premature immune aging. So their biological age is not the same, their actual age is not the same as their age in passport.

When we looked at this phenomenon in the population based setting, we found that even at onset of rheumatoid arthritis, people with rheumatoid arthritis carry two extra years on their backs, as opposed to, again, their passport age, and then they accumulate at higher pace with each decade of life contributing to their shorter survival. So the implication for practice is that premature aging contributes to risk of rheumatoid arthritis and can also influence decreased survival. What do we know about mortality in people with rheumatoid arthritis? Historically, the association between having RA and the risk of dying has been summarized as about 1.52 fold increase in mortality. And I am presenting this historic data from cohorts from the Rochester Epidemiology Project before 2000s, and then the RAD cohort, Australian cohort with data at or after 2,000.

You can see that mortality gap widens over time after RA onset, and historically it's been at about five years after RA onset we've noticed increase in excess mortality in RA. In more recent cohorts it's about ten years, but the point is that the longer duration of rheumatoid arthritis takes away more years of life. Excess mortality is also not uniform across different ages. We know that the gap is wider in younger and middle aged individuals who have, the baseline rate in the population is pretty low for mortality at that time, as opposed to older individuals where, of course, the propensity for dying is higher both in RA and in the general population. Does it affect, does the increased risk of mortality affect everyone with RA?

Not quite so. About twenty five percent of people, and we'll discuss specific categories, would experience this premature deaths. So being aware of increased mortality in people with rheumatoid arthritis, in particular in those who are younger and who's had RA for longer. What happens with trends in mortality over time in people with rheumatoid arthritis? Globally from global burden of disease framework, we know that there has been a decline in mortality rate or cause mortality of about twenty four percent over the past three decades of calendar time, and the largest decline happened in high income countries.

We observed very similar trends in Olmsted County, Minnesota, and there's been very similar observations also from the national data, veteran health data, where we see that the risks have declined in the past twenty years. So good news is that mortality risk in rheumatoid arthritis has declined after two thousand, corresponding with all the successes of the treatments and approaches, improvement of approaches to treatment of rheumatoid arthritis. What contributes to increased mortality in rheumatoid arthritis? Well, first one thinks whether there is something genetic or something related to families. Swedish studies show that full siblings of patients with rheumatoid arthritis also have increased mortality.

That's very interesting. It's not quite as increased than in people with rheumatoid arthritis themselves, but higher than compared to siblings of population based comparators. Moreover, this excess mortality in siblings with rheumatoid arthritis attributes to both seropositive and seronegative patient's siblings. So there's some shared familial influence on mortality risk that goes beyond RA disease effects and actually starts beyond RA disease effects. HLA DRP1 inheritance was evaluated for potential association with mortality.

Some haplotypes do associate, but not all. We do know that carriers of HLA DRB1 do have signature of premature immune aging. So there is something there in genetics that can contribute to reduced mortality from the get go, from increased mortality from the get go for these people with rheumatoid arthritis. What about characteristics of RA and specifically serologies? People who have seropositive rheumatoid arthritis do tend to have increased mortality risk, and that is dose dependent to the titer ACPA or rheumatoid factor serologies, as well as has been shown in some studies, specifically in BRAS registry to be associated with high mortality if a person is dual positive, aqua positive and rheumatoid factor positive.

Other studies have actually shown that even being positive for just rheumatoid factor associates with high all cause mortality independently of aqua presence. In the RAP cohort, we observed that this disadvantage or excess mortality that associates with positive rheumatoid factor has been pretty stable over several decades and has not significantly improved despite the advancements in treatment. Similarly, for the NHS data from Doctor. Sparks study, seropositive patients who are positive for rheumatoid factor or ACPA had adverse mortality experience as compared to non RA populations as well as to serone active patients with rheumatoid arthritis. Data again from BRAS study have shown that exposure to BDMARs but not conventional synthetic DMARs may help alleviate mortality risk in people with seropositive rheumatoid arthritis.

That's a curious observation, interesting whether or not that's mediated in part by controlling inflammation, but requires more investigation. The bottom line is that serostatus can be used as prognostic factor not just for disease, but also for survival outcome. A very nice study from the rabbit cohort that associated inflammatory burden and mortality experience. So in this study, the researchers showed that patients with persistent and highly active rheumatoid arthritis tend to have higher mortality, but also inherently lose more years of life. And so in a person who's been at DAS 28 on average above 4.1 or higher, they can lose up to ten years of life due to this inflammatory burden.

Studies from Norway evaluated how much CRP, chronically elevated CRP contributes to excess mortality risk and concluded on about twenty five percent mediation of the effect by CRP. Of course, is many interacting factors and it's difficult to disentangle which one contributes and apportion the specific number to that, but there is this data out there. What we do know is that certainly the burden of inflammation contributes to adverse survival outcomes in people with rheumatoid arthritis, and thus it's one factor that we can potentially control with treatments. Other important factor is presence of extra articular manifestations. We do know that people with extra articular manifestations tend to die prematurely and you can see on the graph here, the blue line falls pretty dramatically.

These are people with all patients with extra articular manifestations. Again, data from Olsen County Rochester Epidemiology Project. By ten years of follow-up, about forty percent of them would be dead as opposed to people with rheumatoid arthritis without extra articular manifestations where mortalities twenty five percent at that point or in the general population where only twenty percent of people would be dead by that time point. So quite significant increase with the presence of XRA, particularly severe extraarticular manifestations, but even non severe do contribute. So poor prognostic marker if someone has extraarticular manifestation in terms of their survival.

Interestingly, even though we see improvement in incidence of extra articular manifestations in rheumatoid arthritis and they're becoming much more rare as compared to previous decades, Mortality from extra articular RA has not decreased. So extra articular RA continues to be as deadly as it has been prior to February. There hasn't been any meaningful or statistically significant, rather, change in that outcome. So it contributes to persistent excess mortality in patients with rheumatoid arthritis. And here we come to the cost specific mortality.

And I'm asking you a question, what is the two most common causes of excess mortality in rheumatoid arthritis in your view? Infection and malignancy, cardiovascular disease and malignancy, cardiovascular disease and pulmonary, GI and endocrine. I'll give it another couple of moments. There is definitely a couple of teasers, but overall we'll discuss, let's get it up to maybe 25. Yeah, very good.

So the trend is clear, more or less. Cardiovascular disease and pulmonary is the winner in your opinion, and then second is cardiovascular disease and malignancy. And infection and malignancy takes the third place. Okay, so there's very nice data from veterans, from veterans from their registry by Tate Johnson that evaluates causes of mortality and concludes on the fact that mortality, especially in recent years, is mostly explained by cardiovascular and respiratory mortality contributing to up to seventy percent of mortality in rheumatoid arthritis. Specifically, one most overrepresented cause of death in rheumatoid arthritis that is not nearly as common in the general population is ILD and ILD related to RA, of course.

As we've seen improvement in all cause mortality, cardiovascular mortality and even some trend in cancer related mortality. There hasn't been such trend in respiratory mortality, unfortunately. Speaking about cardiovascular disease, we do know that RA associates with increased risk of heart disease up to about one point five, one point six fold increase with coronary heart disease and heart failure being the major contributors. Again, the risk is higher in people who are seropositive, particularly aqua positive, but also RF positive too. We've seen decline in mortality from cardiovascular disease mostly driven by coronary heart disease improvement and a decline in incidence of coronary heart disease after two thousand.

And this has been shown in our cohort as well as in cohorts from Western Europe. Do all people with rheumatoid arthritis currently benefit from this improved profile of cardiovascular outcomes? So, it appears that people who respond to treatments and who get control of RA disease certainly are in a better position than those who don't. This study shows data from Swedish Biological Registry and specifically incidents of acute coronary syndrome in people who are users of TNF inhibitors. These are graded by ULAR DUS 28 response responders that are in the white diamonds tend to have risks similar to the general population of acute coronary syndrome as opposed to those who did not respond completely to TNF inhibitor use.

So, it certainly puts a plug again towards treatment. There hasn't been any specific medication that is particularly advantageous for cardiovascular outcomes as opposed to the other, but it's more the effect of treatment itself that has been associated with the benefits. Despite improvement in incidence of coronary heart disease, we haven't observed similar improvement in incidence of heart failure in rheumatoid arthritis, which is a major contributor to cardiovascular mortality in RA. So that has not improved, unfortunately. So general trend in cardiovascular mortality in RA is towards improvement, but those who have uncontrolled or untreated or longstanding uncontrolled RA are at disadvantage from standpoint of cardiovascular mortality.

So lung disease is our next topic and lung disease associates with two to three fold increased mortality, especially again in seropositive individuals. In studies from Olmsted County, we observed that survival after onset of RA ILD, median survival is about seven, eight years only after the diagnosis. You see the precipitous decline in survival, the solid line on the graph, in people with RA ILD as opposed to patients with RA and no ILD. There are other manifestations including RA associated bronchiectasis, COPD, and such that also significantly contribute to worse mortality. In general, of course, respiratory mortality, lung disease is on everyone's mind these days, and we don't have a very good solution in terms of solving that problem yet.

So the answer to the polling question is cardiovascular disease and pulmonary are the two most common causes of excess mortality in rheumatoid arthritis. Speaking about comorbidities as a whole in terms of their contribution to mortality in rheumatoid arthritis, this study involved sixteen hundred people with rheumatoid arthritis and matched comparators from the general population who were using latent class analysis classified into clusters based on their morbidity count. And you can see that the lowest number of morbidities are in the red cluster, here in the left lower figure. And then we associated these clusters with survival. In the right upper corner you see the figure of survival.

So two points that are important from this study pertinent to this talk is that first there is a cluster of patients with rheumatoid arthritis, forty two percent, that have particularly favorable outcome, and these are in red, so they have low mortality rate and they have survival similar to the expected rates. So they are no different from the general population in their survival experience. They tend to have higher emission rate and doing very well. So there is a real category of patients who do quite well. And then there is a category of very unfortunate individuals, cluster four in purple.

You can see that it's minority, eight percent. They have very unfavorable outcome in terms of survival. You see the drop in survival on the right hand side where purple curves clearly separates from all other clusters. And so these patients tend to have a very high number of morbidities. They use more glucocorticoids, they are less likely to use disease modifying drugs, they have highest mortality.

So definitely a variety and heterogeneity of experience in terms of mortality in people with rheumatoid arthritis. There is a chance for a very benign outcome and unfortunately accumulating morbidities can be associated with very poor outcome. Another metric that can be used as predictor for mortality is frailty. And this is one of the recent studies from Kate Weishman's group that shows that frailty can be used to prognosticate mortality and is acting in a stepwise fashion where mortality risk increases from more robust individuals to individuals with severe frailty. That phenomenon has been noted across different age groups suggesting that this really captures biological vulnerability and is not fully explained by chronological age.

The contribution to this association is particularly significant from morbidities and functional deficits. What about the elephant in the room and how DMARTs affect mortality risk in people with rheumatoid arthritis? The bottom line is that if RA is untreated or uncontrolled, mortality is increased. And we've seen this with historic data that there is a significant and quite dramatic association with poor survival. Use of DMARDs including that of methotrexate, this is data from pooled met analysis showing that it associates with lower all cause mortality, cardiovascular mortality, RAILD mortality, so all the major contributors.

TNF use associates with reduced or at least similar mortality as compared to conventional synthetic DMARDs such as methotrexate, that's using RCT data and observational data. Combining biologics with methotrexate as opposed to using biologics by themselves does not increase mortality, so combinations are fine. JAK inhibitors is a little bit of a question and that relates to the oral surveillance study data and primarily for tofacitinib versus TNF inhibitor comparison relates to mostly high cardiovascular risk patients. The long term data are limited and required for this study. So use DMARDs to manage rheumatoid arthritis as appropriate and that is probably well set to increase or to provide at least better prognosis for survival in people with rheumatoid arthritis.

Another medication or group of medications that is, class of medications that is very important is glucocorticoids. Here the association seems to be dose dependent, although there is a trick to that which I'll allude to. So the higher the dose, and specifically daily dose eight or higher, associates with progressively increased mortality. And this is data from the study. All cause mortality and cardiovascular mortality are increased the higher the dose of, daily dose of glucocorticoids used.

So the question is, are lower doses safe? And this really relates on how long you use steroids. If the dose accumulates to above forty grams, it also associates with significantly increased mortality risk overall and cardiovascular mortality. Yearly accumulation of five gram or higher also associated with over two fold mortality risk in that study. This risk is particularly high in people who have rheumatoid arthritis and diabetes as opposed to RA and no diabetes.

And speaking about diabetes, so GLP-one receptor antagonists are on everyone's mind these days. Compared to gliptins, they seem to associate with lower all cause mortality and MACE people with immune mediated diseases, including rheumatoid arthritis, in those who had concomitant diabetes. The magnitude of reduction in this risk is similar to a population of people with diabetes. So there's nothing very special about having RA and using this GLP-one receptor antagonist in terms of mortality benefit. But overall it does associate with reduced mortality in RA plus the type two diabetes.

So the bottom line is minimizing the use of steroids, minimal doses for shorter duration should provide the most benign outcome from a mortality stand point. Now we'll get to the second poll question, and I'm showing you profiles of several patients with rheumatoid arthritis. Which of the following patients with RA is at the highest long term risk for all cause mortality independently of age? A, a 62 year old woman with serinegative RA, low disease activity, obesity, well controlled hypertension on methotrexate. The second is 45 year old man with serinegative RA, former smoker on methotrexate, episodic RA flares treated with a burst of glucocorticoids, no extra articular disease.

Next one is 54 year old man with seropositive RA long standing disease, extra articular manifestations including lung involvement, moderate RA disease activity despite the use of methotrexate and biologics. And then finally, 70 year old woman with seropositive RA in sustained remission on biologic therapy and stable coronary artery disease. And it looks like thirty some people unequivocally chose third option which I also agree with. There is a phenotype of patients with rheumatoid arthritis that is particularly unfavorable in terms of risk of death. And that is people with seropositive RA who have high cumulative disease activity, who have extra articular manifestations of the disease, who had chronic glucocorticoid exposure, who are multi morbid.

Those who developed RA at younger age and had it for longer. So definitely not a very good setup from standpoint of lifelong GBT. And here we get to the takeaways from the talk. I would like to stress that uncontrolled RA predisposes to premature mortality, and that doesn't depend really on what area we live in. If RA is uncontrolled, the risk of mortality will be high.

There is improvement in overall mortality in patients with rheumatoid arthritis after 2000s, but it doesn't as much apply to those who have severe disease and particularly those with extra articular manifestations, those who are seropositive with consistent cumulative inflammatory burden. Cardiopulmonary causes account for most of the excess mortality in people with rheumatoid arthritis. Patients with fewer morbidities tend to have optimal survival and can have survival similar to the general population. That is definitely possible. And then effective DMARC therapy is part of mortality risk reduction in people with rheumatoid arthritis going beyond just treatment of RA disease itself, but also providing and gifting them extra life years.

So keep that in mind. With that, I'll thank you and I'm available to answer questions now or during the panel. Thank you. So

if you have any questions now, let's do that. Again, I want to remind people to put your questions into the player. I think they're fixing it right now, there's a little bit of a problem there. And for anyone that wants to do the polling on your phone, I'll remind you of that website. It's roomnow.cnfconference, cnf.io, okay?

So, and that does work well. So if you have a question, please come up to the microphone. I don't have any online just yet, but my question was maybe given the profile that you said of risk factors and whatnot, and then this latter issue of eight percent who have a rapid trajectory and a higher risk of decline and mortality risk, is there a way of predicting mortality risk at the outset, at baseline?

Yeah, so some of these characteristics that are present at onset, including the ones that I mentioned, including early age at onset, presence of extra articular manifestations are positive, track with worse survival going forward. But in terms of accumulation of morbidity, I think one way to predict that somewhere earlier could be using that frailty estimate and grading as robust pre frail, and then based on how profound the frailty status is because it also relates to comorbidity status and functional disability or functional deficits. There's a few different approaches. We definitely cannot anticipate at all times how successful or unsuccessful the treatment course would be for patients with rheumatoid arthritis because cumulative inflammatory burden defines a lot. So there are some characteristics that are clear cut present at onset, but we don't know the behavior of the disease over decades to come.

And that defines a substantial amount of risk.

Microphone, go ahead.

Good morning. I wanted to know what you thought about methotrexate and the link to lower mortality, and is it using methotrexate early in disease that's uniquely associated with lower mortality?

So I just want to understand your question better. Are you asking if methotrexate associates with lower mortality?

No, I know it lowers mortality. I wanted to ask you why you thought that was the case. And secondly, is it simply when methotrexate is used early in disease?

Yeah, that's a good question, thank you. I think part of it, again, relates to control of disease activity with methotrexate, and those who tend to respond to methotrexate particularly early on are in a better position than those who don't respond and go on to try a more advanced medication. So I'm not certain this is necessarily again a medication specific effect, but more of an inflammation control and matching of that medication to a profile of a responder to this medication. We know that people who do require biologics, especially early on within the first year, tend to do overall not so well, not because of the biologics, but just because of their disease may be more aggressive.

Thank you.

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