RheumNow Podcast - Death & Surgery Save

This is the RoomNow podcast for the 02/22/2019. Hi. I'm doctor Jack Cush, executive editor of roomnow.com. This edition is brought to you by RoomNow Live. Great rheumatologists like us go to great rheumatology meetings like this.

It's in Fort Worth, March 23 through '24. This edition has got a happy title. It's not death and taxes, it's death and joint replacement surgery. Sorry for the downer, but it's the best I could do. Let's start out with a population from Sweden, a population study from Sweden that actually looked at mortality rates in patients with rheumatoid arthritis, and also patients who have general musculoskeletal diseases.

They did sort of an ICD-nine kind of ICD-ten kind of search on their population. This is from one region in Sweden, S K A N E Skahn. Sorry if I did that wrong. And they looked at the patients, the population, and they found amongst the RA patients and amongst the, those with musculoskeletal complaints and disease that the standardized mortality rate was two point two fold higher in RA patients compared to those who didn't have RA and one point five fold higher in MSK patients compared to those who did not. That mortality rates were actually higher in those who had less education.

And this has been pointed out by Ted Pincus and others in the past, especially when you consider those with less than nine years of education versus those who had greater than twelve years or equal to twelve years of education. Now why is education a determinant for, better outcomes, and if you don't have it, poor outcomes? Again, it's really not well explained and it's other studies have shown it's not an access issue, or that they're better patients. There's a sort of a multifactorial reason. It's the same thing for lower socioeconomic status.

My view is we don't know and if I had to guess at this point, my crazy guess is going to be it might be related to diet and microbiome. That those with less education, those in lower socioeconomic groups don't eat as well and maybe that's an important factor in not only getting disease but how the disease has played out. We'd like to see more research on this. Another study looked at mortality rates in an RA registry, of over almost thirteen thousand RA patients. They found twelve, fifteen hundred deaths.

They follow these people prospectively amongst a total of what was it eighty thousand patient years of follow-up. They found that mortality was most strongly associated with BMI greater than 30. And when that was seen, and that was seen early actually at age 30, where there's a twofold increase in mortality. It continued on in older age, although not as strong. So obesity, another risk factor for mortality.

And so again, why it's really not clear. You know, is data about those who are the most obese actually not having higher death rates. It's really those who are obese and those who are actually very, thin who have the highest death rates in rheumatoid arthritis. But obesity is a risk factor. It's a risk factor for getting disease, a risk factor for having more severe disease, it's a risk factor for having less response to usual therapy.

So here it's a risk factor also for mortality. In Australia, they did an analysis of almost a half million total knee replacements, and found that revision rates were actually lower in RA versus OA, but that, the risk of infection was higher in RA patients. And I think that this is, a trend. I think that the there's a more selective, use of surgery in rheumatoid arthritis these days. Patients are better treated.

They're probably going to surgery with a need for surgery, but maybe a little cleaner. They're better managed with more aggressive therapy. OA really the therapy and the outcomes in OA really haven't changed that much in the last several decades where it has changed in RA, so it's therefore not surprising that the outcomes of surgery would be better in RA compared to OA and that's just looking at knee replacement surgeries. A study from Finland looked at almost 4,000 JIA patients and compared their outcomes as they got older to normal population controls. In that cohort, the mean age at death for those who did die was 20.3 years of age, and they showed that the death rates were not increased in JIA patients who, as they grew as they grew up, that they basically had the same rates of death, but what was different were the causes of death.

Whereas, normal population, normally young individuals, adolescent children, young adults are more likely to die from suicide. The JIA most common cause of death was accidents. JIA patients also had less substance abuse and less depression and again those being linked in their own way to, death rates in non JIA patients. So interesting data and I think that it's good data and it says that we're doing a good job in managing our JIA patients. Another study looked at hospital deaths and what the cause of hospital deaths were for anyone who goes into the hospital.

Turns it turns out this population based study shows that fifty three percent of hospital deaths are related to sepsis and that thirty eight percent, thirty five percent sepsis is the most is an immediate cause of death. And this is a record review from six academic centers. Again, when you go into the hospital, that's the outcome that scares everyone, that as a complication of whatever disorder you went in for, you could get infected and might die. They didn't go into risk factors in this particular study but I think it was a sort of an eye opener as far as the number or the percentage of deaths due to sepsis in this population study. We have some articles in the room now this last week.

Yesterday we had an article from Greg Silverman published in an Alzheimer's rheumatic disease about his research with the lupus patients and the analysis of the fecal microbiome. He presented this data at the ACR last year, it's now in print, it's a very interesting publication at sixty six lupus patients in whom they studied their microbiome and sort of looked at other things including serologies and clinical activity, etc. They compared that to 17 normal controls that were age matched. What they found in the lupus patients was a fivefold higher rate of a particular species of the Rheumatococcus navis, that's RG, Rheumatococcus navis. What they found was that those who had overgrowth and it was again five fold higher in lupus patients, the ones who had that, they were more likely to have flares.

That disease activity was associated with increases in anti RG, anti Rheumatococcus Navis antibodies and again it correlated very well with not only the sleet eye but also with double stranded DNA levels and inversely with complement levels. So the other interesting thing showing again the microbiome might very well be associated or correlated with lupus activity is that the highest levels of RG, Rheumatococcus Nervous antibodies were seen in those who had lupus nephritis, suggesting that these perturbations in the microbiome, leading to a specific pathobiont might be driving disease. On the other hand, it might be a consequence of driven disease, and that was not necessarily worked out by this study. But I know we've had a lot of research on the microbiome, very little being done in lupus. That's why, this report by Doctor.

Silverman is I think sort of very interesting and worth the review. Another big, ticket item occurred on Wednesday. Actually, announcement came on Tuesday where Pfizer made an announcement about a safety warning concerning high dose tofacitinib use. This came from the DSMB of a large prospective safety study where patients were being on with RA older over the age of 50 with cardiovascular risk factors on methotrexate were enrolled to either receive five milligrams BID or ten milligrams BID of tofacitinib or TNF inhibitor and they were followed for a long period of time, you know, three years plus, looking for what happens as far as safety outcomes in this particular study. The warning stems from the DSMB noting that amongst those who are taking ten milligrams BID, the dose that's not in use in RA or PSA in The United States, actually had a significantly increased rate of pulmonary embolisms and a higher rate of mortality.

So that was a bit surprising, not necessarily, expected. The recommendation from the DSMB and from Pfizer to the study sites was to take your patients who are on ten BID and either stop the drug or lower the dose to five milligrams BID. Those who are on a TNF inhibitor were unchanged. There are other studies that are going on with, tofacitinib and other conditions are not going to be affected by this nor should your patients who are taking this in your practice. Since this is an unapproved dose, you shouldn't be using ten milligrams BID given this warning is out there.

Again, the question now is since this joins some of the data that's been reported for baricitinib on venous thromboembolic events, PEs, DVTs and whatnot. Is this related to the JAKs or is this related to these drugs? Will we see this in other JAK inhibitors? Again, the bottom line as far as I can tell so far is the following. Number one, that having an inflammatory disease like rheumatoid arthritis increases your risk of blood clots, VTEs, DVTs, and PEs period.

It's seen in a number of different autoimmune conditions. Second, the contribution of therapies doesn't seem to be all that consistent. The question lately has been, do the JAK inhibitors do this? A little bit of a suggestion with baricitinib but you follow them out at both doses and the current approved dose of two milligrams doesn't seem like it's increased. The tofacitinib, this was not even in their label.

And when they did a review of this and posted this at the ACR meeting in 2018, it didn't look like they had anything higher than background rates. In fact, they were lower than TNF inhibitor rates. So this finding in this study, the study that was stacked in favor of cardiovascular events, is surprising, but then again, maybe not. There are other studies that occasionally show methotrexate has a higher rate. But again, the rate you're looking for is basically 0.5 events or lower that sort of that wouldn't be due to drug.

And that's kind of what we're seeing here for most of these reports. This particular critical safety warning given by, Pfizer did not have any true numbers and we'll have to wait until the report comes out or it is published. Lastly, actually two more reports. One, hip replacements lasting twenty five years. What?

You're kidding? I don't know about you, but when I started in rheumatology, you know, all the orthos were saying, you know, a hip replacement is gonna last, knee replacement is gonna last ten to fifteen years. They're still saying the same thing. I had my knees replaced in 2011 when I pushed my surgeon. He said, you know what, if you treat it right, it should last thirty years.

So this is actually a study that was done, actually it was a literature review that was done over a 116 papers. They narrowed it down to 44 studies over I think 13,000 patients, and basically the pooled survival of hip replacements was eighty nine percent at fifteen years, seventy percent at twenty years, and fifty eight percent at twenty five years. Hip replacements are going to last twenty five years in the vast majority of your patients. Again, there's no data out there right now like this for knees, there's actually, there is some, it's sort of scattered, but the data is very good and I think that you should tell your patients that these should last, know, twenty to thirty years if you're an ideal candidate, if you don't mistreat the implant, if the surgery is a success. We'll end it with a report about the survival of, interleukin one inhibitors in my favorite condition, systemic JIA.

This is a study of Italian study following patients for over fifteen years. I think it was about 77 patients in their study. Some were treated with Anakinra, some were treated with Canakinumab, and basically they showed that there was no significant difference between survival of one drug in an or another with systemic JIA. However, if you look at the graphs, the p value was 0.058, so a trend towards, or favoring canakinumab survival more so than Anakinra, maybe that's because it's a longer acting drug. Some of the other, factors that we're seeing here, you actually had better survival on the IL-one inhibitor when it was your first IL-one inhibitor and not your second or third biologic.

And then adverse events were actually more likely in those who had previously been treated with another biologic. The bottom line is that the use of IL-one inhibitors seems to be quite successful in systemic JIA patients with a good survival and if used early, reduces the risk of non adherence or dropout or even adverse events. So that's it. Go to the website, check out these reports and more. We'll see you next week on the RheumNow podcast.

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