RheumNow Podcast TNF's Role With The Inflammasome (1.25.19) Save

You know, this is my fourth try at doing this recording. Not sure what's wrong with my mouth. It usually fails me. Maybe on the fifth time, it'll save me. Hey.

It's the 01/25/2019, and this is the Room Now podcast brought to you by Room Now. Live. In today's report, we're gonna discuss seropositivity. What happens to rheumatoid factor and CCP when you use effective therapy? Also, smoking, does that affect outcomes?

We'll look at a cohort of rituximab treated patients and figure that out. And I know you're all dying to know, wondering, staying awake at night, does an IL-one driven auto inflammatory syndrome respond to TNF inhibition? We found the study for you that's going to answer that question. So let's start with a study, a meta analysis of IMiD patients that includes a large cohort of RA patients, inflammatory bowel disease patients, and psoriatic arthritis patients who are on biologics, specifically 13,000 plus. And it compares that actually, it's 4,719 and compares them to a younger cohort on biologics, 13,000, and three almost 4,000 older patients not on biologics.

And specifically, they're looking at the issue of age and biologics and the risk of infection. So they're gonna compare the elderly that are on biologics with the elderly that are not on biologics and compare the elderly to younger patients and see what's going on. What they found was maybe not surprising was that there was a higher risk of infection when you looked at the elderly population. Now, one of the problems of this report is that many of the reports they included in the meta analysis included variable definitions of infection. It wasn't just serious infections or hospitalizable infections included in some reports, all comers, but I think the message is maybe, powered by the numbers.

And so the bottom line here is that there seems to be a 3.6 higher risk of all infections when you're elderly and you're on a biologic. And that's comparing you to elderly people not on a biologic or even younger people. Now this did pan out also for pneumonia, a serious infectious event where there was again about a threefold higher risk. This data is maybe helpful, but also scary. You know, one of the biggest problems with the elderly is they tend to be undertreated when it comes to aggressive therapies, combination therapies, and especially biologics.

Yet there's very little data that says that they don't respond as well or that they're really at much higher risk. So here we're talking about elderly people mainly having a higher risk of all infections. That includes nonsense infections, URIs, and things like that. But elderly people bring with them a higher degree of comorbidities, and comorbidities plus a biologic may give you a higher rate. So the bottom line is I think you have to be careful in selecting selecting the patients who do get biologics, and I would tell you not to shy away from giving them to the elderly unless you think they have too many risk factors.

I came across an interesting study about auto inflammatory syndromes, and specifically, there's a a journal of clinical investigation report that looked at a, knockout mouse model of familial Mediterranean fever, where they're looking at pyrin and and the inflammasome and how that drives inflammation that we, that we would recognize as being part of that syndrome. Specifically, looked at the interplay between the inflammasome and TNF. And what they showed was that this in this mouse model, it had very high TNF levels. Interestingly, when they automatically developed the upper inflammatory syndrome, that they found that TNF was overall a very important modulator of pyrin and inflammasome activation. And and and that and that was previously not, I think, appreciated.

Again, we think of the inflammasome being activated by a number of different mechanisms that driving caspase activity and unregulated IL-one release. And that's why the IL-one inhibitors work so well in the inflammasomeopathies, the auto inflammatory syndrome, Still's disease, Schnitzler syndrome, there's a million of them. But again, FMF is a really good example. But yet if you look at that literature like I have, you see reports of people who didn't respond so well to an IL-one inhibitor, but were given a TNF inhibitor and boom, they responded really well. Well, I think this data suggests why a TNF inhibitor could be useful in someone who has an auto inflammatory syndrome.

I think it should be tested in the clinic, with an actual clinical trial, But at least this is animal data suggesting maybe a mechanism that could be useful. So next is an interesting study that looks at people's perception of cardiovascular risk, specifically those rheumatoid people. Looked at almost 500 patients, in a systematic literature review, and looked at what were their perceptions about cardiovascular risk. And we know RA patients are cardiovascular risk. Many of you talk to your patients about that risk and use that risk as a means of being maybe more aggressive and knowing that if you use, effective therapies like methotrexate or like a biologic, like the TNF inhibitor, that you can reduce the cardiovascular risk in patients with inflammatory disease like rheumatoid arthritis.

Well, in this particular study, they showed that somewhere between seventy three and ninety seven percent of patients were unaware of a significant cardiovascular risk due to their disease. So yes, you're doing them a favor by telling them this when you're educating them. And yes, you're doing them a favor when you tell them that effective therapy, many of the drugs that we use can actually lower that risk. And I think that there's a big knowledge gap that's out there with regard to what happens. We know that chronic uncontrolled inflammation drives cardiovascular.

It also drives infection, also drives, cancer risk. So again, we should talk about how systemic inflammation is a really bad thing. And, you know, patients need a reason why they're going to take your therapy, why they're going to fill your prescription. And I think sometimes having this kind of discussion could be most helpful in getting them motivated and getting them to trust you to go out there and actually fill that prescription. So there's an interesting study about, from JAMA about the use of marketing to drive prescriptions.

Uh-oh, in this case, it's opioid prescriptions. So this recent JAMA study looked at when drug companies were involved in, promotional activities to promote opioids, they found that very little goes a very long way in not only promoting sales, but also driving up opioid prescriptions and opioid deaths. So the numbers that were quoted in this article were when a company increased its budget for marketing by $5 per 1,000 patients that the number of opioid prescriptions rose almost doubled. It rose eighty two percent and the number of opioid deaths increased nine percent. Yikes.

You know, this is, there's enough problems with opioids and the opioid epidemic and opioid overdose without knowing that companies, have in the past been driving this with their marketing efforts. So, again, there's a lot of a lot going on right now to rectify some of these past evils. And, and obviously it's showing up with most of you not even prescribing opioids anymore. So this is kind of scary data. The National Inpatient Sample.

This is a study of patients who get hospitalized and a recent study of patients in the NIS between 1998 and 2014 showed that when gout patients were compared to other patients going into hospital for joint replacement surgery, they incurred as much as a 20% higher total health care cost and utilization. And that there was a strange number of a six percent higher risk of in transfusion in patients with gout. That one I don't understand, but I do understand that gout patients may bring to the table a higher risk, a higher rate of maybe, complications, including gout attacks, but other things because of their many comorbidities suggesting that again, this is a special subset, especially when they're hospitalized. And unfortunately there aren't enough hospitalists who are really good at gout and there aren't enough rheumatologists who are going to the hospital. So this is another unmet need out there.

So I had two other reports that I wanted to bring to your attention. One was a report on seropositivity. This is a sub analysis of the improved study, is a relatively early RA patients where patients were started out on, steroids and methotrexate. And if they didn't achieve a DAS of less than 1.6, they had their dose changed or they were randomized to either receive, triple DMAR therapy, add on therapy sulfasalazine and then, hydroxychloroquine or an add on adalimumab. And in this study, they collected a lot of serum and they specifically looked at what happened to rheumatoid factor CCP and anticarbamylated P or CAR P antibodies.

And they looked at all kinds of variants of that. In total, it was 14 different auto antibodies they could look for around in some way or another connected to rheumatoid arthritis. What they did see that was when you used effective therapy for most of these patients, rheumatoid factor, CCP, even CAR P dropped, but then over time it would start to escalate and seen that the only things that were consistent in this study was that the addition of immunosuppression or effective anti inflammatory therapy with more drugs was associated with a further drop and that the subtraction of therapy with drug withdrawal, which is part of the protocol was associated with an increase in autoantibody levels. Yet, in spite of these changes, none of this correlated with either DAS responses or EULAR responses, suggesting that while effective therapies are good at driving down inflammation and may temporarily drop seropositivity, this is not what drives the clinical response. Now, are some therapies out there which we think are really good and may drop, their rheumatoid factor association with clinical responses that includes, rituximab and some studies with abatacep.

But again, I don't know that this data other than being interesting, I don't think it still moves me to do anything more than one seropositive test. I do rheumatoid factor and CCP. I sometimes do a fourteen thirty three ADA. I don't have access to anti CAR P antibodies, but I think that I do them once and then I'm done. I don't really want to know if they went down, you know, if it's high, it's high.

If it's 100, it's 100. You know, who cares if it changed 20%? Kid, which obviously what matters is whether or not the patient gets better. But this is an issue that's going around and now you know the rest of the story. So lastly, smoking.

You know, we do know that obesity risk factor for RA, you know, worsens RA. We do know that, alcohol is actually something that can help rheumatoid arthritis in moderation, of course, but it's not necessarily a risk factor for anything. And certainly smoking is a bad risk factor for developing the disease, but does smoking actually impair clinical responses? So there's a group in Europe, a number of investigators led by Ron Van Vollenhofert and others who have a registry called the SORARA registry. It's a rituximab registry, has multiple functions that have been used.

And in this, study, they looked at 528 smokers versus almost 2,000 non smokers and looked at what happened to, the clinical responses over time. At six months, disease activity was roughly the same in the smokers compared to non smokers. There were no significant difference differences with regard to change in DAS. The P value was 0.41. EULARI's good responses were again about the same.

And while smoking didn't seem to predict outcomes, other factors like ACPA baseline dash 28, PAC, and even use of conventional, disease modifying drugs were better predictors of an overall good response. So certainly we want to encourage our patients to stop smoking. This is one of several studies that have looked at this. So there are some other studies that do show that smokers do have a poor outcome, but in this particular study, looking at rituximab, and they didn't look at any correlation by the way, between smoking and rheumatoid factor and clinical responses, you might consider a rituximab trial. But nonetheless, I think this says that, at least we know smoking is a risk factor.

If you change smoking behavior, would it increase clinical responses? It seems like a prudent thing to do, but this particular study did not back that up. So that's it for this week. Go to the, website to look at these citations and read more about these reports. I'll encourage you to go to roomnow.live, where you can come for the education and enjoy the fellowship and the FaceTime with the faculty, who will be there at the whole meeting.

And then it's gonna be a fun meeting. You know, we start on Friday in the afternoon. We're gonna, have a, reception after the meeting called RheumNow Distilled. We're gonna have craft beer, craft whiskey, and craft lemonade. I'm going for the craft lemonade.

And on Saturday night, we're gonna have a great rooftop reception, a Tex Mex reception, that you're really going to enjoy. You're gonna enjoy the speakers. Go to the website. See who the speakers are. It's gonna be a brainstorming two days in Fort Worth.

RoomNow. Live. We'll see you next week on the podcast.