TNR Safety Of Biologics Save

Everyone. This is Tuesday night rheumatology. Actually, it's the inaugural Tuesday night rheumatology, our grand round series. I'm Jack Cush with RheumNow. I hope you were here last week when we broadcast our town hall meeting.

I think it was really informative. I thought our speakers were very honest, very engaging, really smart. It's been viewed by over 1,000 people since we broadcast it last Thursday night. It is available on the website. But for the next two months, we're going to be doing grand rounds on Tuesday night at this time, 8PM Eastern Time, 5PM Pacific Time.

And I'm going to start us off with a lecture on the adverse effects of biologic and new agents. The normal format for these events is that I'll open with some news. I'll get into the Grand Rounds lecture, introduce the speaker. We'll do a thirty minute lecture, no more than 30 slides. You're welcome to ask questions in the Q and A tab beneath your screen.

Press on Q and A and you can enter in your questions. And at the end of the lecture, I will go there and kind of go through questions. Hopefully, they pertain to the lecture that we're doing today. Not much to report about in the news. Many of you had many questions after our broadcast last week about the coronavirus crisis that we're in, and continued questions.

We're collating them, collecting them. We're thinking about doing another town hall. I don't want to do one right away because I want us to learn a little bit more, maybe three, four more weeks of information. Then from that, we can maybe reconvene some of our prior speakers and get some new ones into more questions from you, the audience. Without further ado, I'm going to show you my presentation on adverse effects of biologics and novel agents.

This is not a CME lecture, we're working on CME and whether or not we can use CME in this format. It's not as easy as it seems, but we're considering it. But this is not CME. Realize nonetheless that I do have conflicts. I didn't put the conflicts slide in, I should have.

I basically have done research and been a consultant for all the products I'm going to speak about now as they were being developed. I do not do promotional lectures for any of the companies. So let's talk about safety. Safety is sort of the big issue that most of us have to deal with, especially in and around the subject of biologics and newer therapies. For me, the real issue here is what are the rules that you have to live by?

I want to impart upon you my rules for dealing with safety that I've learned over the years. Number one, you got to tell patients this line. The longer you're on a drug, the safer it becomes. And you need to wrap your head around that, but it's generally true for the drugs we're going to talk about today, meaning that all the serious adverse events that you're really concerned about are things that are going to appear early on in treatment. In the first six months for most cases, sometimes a year.

And after that, these events can happen, but they're much more sporadic. One, they will have happened early, and two, if they happen and were severe enough, the patients who were susceptible would have dropped out. Depletion of susceptibles leaving those on the drug who are likely to continue to do well. And therefore, they're going to not only just do well as far as efficacy, but they're going to continue to do well as far as safety. So that's an important concept.

Patients on methotrexate need to hear that. Patients on combination need to hear that. Patients who are on etanercept and adalimumab need to hear that because they think the longer I'm on the stroke, oh man, I'm just killing my biology, I'm destroying my immune system, I'm gonna die because of the television ads, say all those things. And it stews in their brains and really gets in the way of future success and compliance and really how they're gonna do. You need to get over that point.

Number two, lower doses are not safer. Lower doses are less efficacious and less efficacy means more problems. Three, the riskiest thing you can do is play it safe. Under treatment is a bad thing in an aggressive disease like rheumatoid or lupus or polymyositis or whatever. Number four, never let someone who knows less than you do about your drugs manage the situation.

That includes the oncologist, the obstetrician, the pulmonologist, the primary care doctor, because guess what? They're all getting their information from television, not from the papers and the conferences that you're subject to. Lastly, you need to know the numbers that you can apply them to real life and help your patients to get better. This is what patients see when they're thinking safety. It's the risk of biologics versus the risk of the disease.

You need to flip this imbalance. Yes, you can discuss the risk of biologics as shown on the right. But you need to talk about the risk of RA. That in RA, the 800 pound gorilla in the room is the disease that is going to damage your joints, lead to deformity and disability, maybe even premature death. And if they don't take that seriously, then these other things on the right, which are largely one in one thousand risks, are not that important compared to RA.

So you need to have this communication strategy, the 800 pound gorilla approach. Again, patients won't be thinking RA, they're going to be worrying about that pharmacy printout, eight pages of nonsense that don't apply, often listing things that are one in five hundred to one in ten thousand risks, but they're going to be swayed by the small print. Again, you need to talk about the 800 pound gorilla rheumatoid arthritis versus the flea, that one in one thousand risk for PML or for an opportunistic infection. You need to clearly portray the magnitude of what the patient needs to consider. You need to compare the two.

And recognize you got to do this simply and succinctly because the more you talk, the more info you give, the more pages you give, the more you're going to confuse and obfuscate the situation. This is a real big problem. A lot of patients when confronted with safety issues become doomsday thinkers. They think that they're as likely to get these side effects as anybody else. In fact, they think they're more likely when in fact, they're just the odds of winning the lottery.

Last thing you speak from strength that you know a lot about this drug, you've been studying this, this drug has been studied. It took ten years and 2,000,000,000 or $5,000,000,000 to develop this drug. It's been given to 2,000,000 people and it's been designed just for you, Mrs. Smith. This drug was carefully chosen.

And you need to portray these numbers. Now this is a horrible slide, of course, but this is a really good slide. It comes from Gert Burmester's review of the long term safety of adalimumab over thirty thousand patients, almost 60,000 patient years in many indications. You can see what is that? I think 11 or 10 indications here, beginning with RA on the first column on the left, and going down the line looking at all the side effects that you think about.

And just look at the data, the numbers and what do you see? You see a lot of zeros and you see a lot of 0.1s. I've highlighted for you malignancy, lymphoma, non melanoma skin cancer, and melanoma and everything's a 0.1 or a zero. There's a few 0.2s. Zero point one is a one in one thousand risk.

Zero point two is a two in thousand risk, one thousand patient years. You can see the only big risk is up here for serious infection, three point nine, one point eight, one point zero. That's serious infections, that's three point nine per one hundred patient years. It's much higher, but everything else is really, really rare. But yet this is what drives the thinking or the unfortunate choices that patients may make when it comes to safety.

What's a one in one thousand risk? Opportunistic infections are a good example where it's a one in one thousand to a one in ten thousand risk of developing opportunistic infection with these drugs, TNF inhibitors, rituximab, avatarsopotolizumab, the JAK inhibitors represented here by tofacitinib and ustekinumab as examples. You look at this list of TNF inhibitors, how many cases have you seen of salmonella, nocardia, HIV, pneumocystis and strangoloidosis with TNF inhibitors? I ain't seen them and I use a ton of TNF inhibitors and have since 1995. Now, think there are some that we need to worry about.

Rituximab, I have a number of things listed here, but the risk of TB is probably the most important risk with TNF inhibitors. You can get TB with rituximab and you can get it with tofacitinib. Everything else is really rare as far as TB. With rituximab, you have reactivation of viral infections, especially hep B, not hep C, herpes and zoster has been reported. The main thing that stands out in my mind looking at the safety reports with rituximab is PCP or what we now call Pneumocystis urovecchi.

This is actually not an uncommon thing even in RA. So while I do not prophylax against PCP or pneumocystis in my patients with RA, RA patients going on rituximab, I probably should, and any patient of ours going on rituximab probably should receive prophylaxis. Abitacin, probably the safest of biologics when you look at all of the studies head to head, it seems to pan out having a slight edge over everything else, but really there's not a lot of signal here. Tocilizumab, not a lot of signal. Tocilizumab, we know there's a big signal for herpes zoster where there's at least a four to fivefold increased risk compared to TNF inhibitors.

Uncommon TB, but it has been reported and BK virus is really only in the very early stages of development. Eustekinumab also not much. So that's opportunistic infection. But let's talk about infections in general. What we do know about the use of biologics is that you have a doubling of the infectious risk.

These are the FDA approved drugs for rheumatoid arthritis. I don't have any small molecule inhibitors in here, but the numbers are about the same. Look at the placebo column on the right and then compare it to the biologic and you see a doubling. But that is a non significant doubling, non significant. When you compare the event rates, might be for adalimumab, it might be two per one hundred patient years and it might be three or four per 100 patient years on a biologic.

Two on the placebo, two, three or four, not significant, but it looks like a doubling. That becomes important later on. It's a doubling across the board for all these biologics except for what? Eitanercept and golivimab. It's roughly the same rate between the biologic and the placebo.

So be aware of that doubling that can occur and realize that that may be a problem. So safety events. In the pre biologic era, when we're looking at infections, there was a rate of three to nine serious infectious events per 100 patient years. That means follow 100 patients for one year, you'll have three or four or five or six, maybe even nine, who will end up in the hospital with a pneumonia, meningitis, septic arthritis, something along those lines. In the biologic era with biologics and JAK inhibitors, the numbers are two to six, not really any higher.

But there is this issue of a non significant doubling, that's why there is a box warning in all the package inserts for the biologics and even the targeted synthetics. It says that serious infections leading to hospitalization or death, including tuberculosis, bacterial, invasive fungal, or even viral infections, and opportunistic have occurred. And realize this important line. It says if a serious infection develops, interrupt the biologic until the infection is controlled. Test and monitor for TB in many cases, this is taken from a TNF inhibitor.

In some instances, it says something like you shouldn't give the drug or start the drug in patients who have an active infection. Nowhere does it say if you develop an infection that you should stop the biologic immediately. That's become a convention that's not well founded in any data or practice. So what are the actual risk of developing a serious infectious event? The predictors of SIEs in RA patients include number one, above and beyond everything else is the severity of rheumatoid arthritis.

That means the inflammatory degree of the disease, but also the ability associated with the disease. Those are two big predictors of serious infectious events. Second is steroids, especially when you're at ten milligrams or above. Third is comorbidities and highest on that list are chronic lung disease, COPD, organizing pneumonia, ILD, and then diabetes, heart failure, renal failure, etcetera. But lung disease is a big player because the number one serious infection event in RA patients is pneumonia, more so in people with chronic lung disease.

Breakdown of skin, skin is your number one barrier against infection. So wounds, ulcers, patients undergoing surgery, and then major joint surgery is a risk factor. There is very little risk imposed by DMARDs, methotrexate, combination of drugs, triple DMAR therapy, even cyclosporine. And there is also very little risk imposed by the biologics. Again, it's a small but not significant risk, and I'll show you where that comes into play.

What about steroids? Do they actually cause infection? Recognize that half to maybe two thirds of your patients are on some dose of steroids. In really every disease in almost any situation, steroids in higher doses, we don't know what that dose is when you go from normal to being too normal to too high, but steroids will increase the odds of non serious infectious events, serious infection events, TB and opportunistic infection and wound infections and post op infections, etc. Obviously patients who you don't want to have infections, you'd want to get them off steroids after you control their disease.

Look at this table, it shows you what the risk is based on whether it's a low risk patient or a high risk patient. Low risk means pretty simple disease, fairly well controlled. High risk is someone not well controlled, many swollen joints, comorbidities, hospitalizations, train wrecks. Even with low doses, five milligrams or less, you probably have some risk imposed by using steroids. But a low risk patient is five milligrams, maybe up to ten milligrams, you're not likely to incur a risk.

However, above ten, ten to 15 or higher, it's likely you're gonna have risks. High risk people are at higher risk than steroids add to risk. That's how you should think about steroids. This is also how you should think about steroids, but more importantly, how you should think about the addition of a biologic. And that's led to what we call the rabbit risk score, but you can look that up elsewhere.

Look at this, this is the front row, the gray row, are patients that are on DMARG and TNF inhibitors. This is from the German rabbit registry. And you can see that if you're on low dose steroids on the far left, less than 7.5, not much difference between the two bars, the gray bars. If you're on medium doses up to fourteen milligrams, not much difference between the gray bars. Maybe when you get to fifteen milligrams above, adding a TNF inhibitor looks like it might be more.

But then look at the rows behind, the blue rows and then that brown row in the back. When you start adding in one, two or three additional risk factors, now the addition of a TNF inhibitor adds to risk. So the risk factors are age greater than 60, chronic lung disease, chronic renal disease, a high number of treatment failures, prior serious infectious events. If you had a prior serious infection event, guess what? You're likely to get it again.

So someone really had a hospitalizable pneumonia, they're likely to get it again, especially if they're sick, especially if they're on steroids, maybe if they're also going on a biologic. So this basically says the addition of a biologic is tenuous, difficult, and risky in your worst patients who happen to be the people who need it most. It's got very little risk in people who are you know you're going to control pretty quickly by the addition of more aggressive therapy. So SIE risk is multifactorial and augmented by steroids, comorbidities, prior SIEs, then the addition of the biologic. So my rules, infection risk is more likely related to inflammation and the disease than the drug, right?

And this is a big issue right now with the coronavirus. Everyone's worried about our drugs and what they're doing. Most of our drugs are not really immunosuppressive. We should be worried about the disease and the patient and what the patient's risk is based on their inflammation, hospitalizations and comorbidities. Then our drugs could add to risk, but only after those things are in play.

Number two, everybody gets their education, everybody but you gets their education from television. So we're not going to listen to everybody and you have to tell your patients they're to listen to you, the person who prescribed the biologic. The most dangerous drug is clearly prednisone. Everyone should agree to that. My rules for holding and stopping the biologic is if you're hospitalized, if you have a fever greater than 102, or if you're very immunosuppressed, chemotherapy, cancer, immunodeficiency states renal transplant, and you have a fever greater than 100.5 or 101, yeah, I'll stop.

Notice, I do not stop for URIs, influenza, nonsense infections, non serious infections, because why? It doesn't matter. The drug is going to be around for four to twelve weeks. By then, they're over their infection. It just looks good on paper.

And now the world has these inappropriate practices of stopping drugs. And you know the problems, what happens when the surgeons stop your drug? Bad things. Well, if you feed into this issue of stopping drugs when patients are going for infusion and they got a little bit of a cold or a cough or a sore throat, give it, it doesn't matter. It happened with the first thirty thousand patients going on biologics in clinical trials.

Peter Merkel said, Prednisone is the best drug we have and prednisone is the worst drug we have. Thank you, Peter, for that quote. So TB, the risk of TB in The United States seems to go down every year, it's about four per one hundred thousand. If you look at RA patients in our society, it's about six to seven. So RA imposes a slight increased risk.

This applies to countries like The US, Canada, Europe, UK, Western Europe, Australia. When you go into places where I call them TB land, where TB is endemic, the risk can be as high as two fifty to five hundred, as high as twelve thousand, even twelve thousand for one hundred thousand. People who were born there, people who live there, who go on TNF inhibitors are at much greater risk. The TB and opportunistic infection risk is worsened by TNF inhibitors. TNF is needed to establish a granuloma that protects the bug or walls off the bug and to maintain it.

If you inhibit TNF, you won't do that or you'll break down those granulomas and develop spread of infection that may be quiescent. It's much, much higher with senoprelibrids and not so high with all the other drugs we use, including IL-six inhibitors and JAK inhibitors, etcetera. Although we do test for TB, it's sort of the design of the study that led to that. The number needed to harm with TB is one in five hundred. The box warning for nearly all biologic says that you should screen for TB prior to starting a biologic or JAK inhibitor or a TNF inhibitor, but not all IL-one inhibitors, for instance, and not methotrexate, azathioprine, apremelast, anakinra, rilodicep, rituximab, belumumab, and pegilodecase.

Let's go on to shingles. What's great about shingles is that it's a common thing, we have to deal with it and we have solutions. One third of the population in The United States at least is going to get a reactivation of varicella zoster. The event rate is about four to eleven per one thousand patient years and it goes up with age. On the very bottom, you can see that a normal person it's four, an older OA patient it's ten per one thousand, RA it goes maybe as high as fourteen and it's about the same with RA patient on a TNF inhibitor lupus and GPA is higher.

When you look at the JAK inhibitors, tofacitinib and baricitinib, you can see it's much higher. It's almost four times higher than that seen in RA patients or OA patients. So again, something you need to have a strategy about. Well, up until now, we couldn't use the live virus vaccine in people who are patients who are going to go on drugs that might augment their risk or situations that might augment their risk if they were on a biologic. You could use the live virus, Zostavax vaccine and people on DMARDs and even steroids up to twenty milligrams.

But now we have the new inactive virus, the Shingrix vaccine, developed and approved in 2017, really based on the ZOE 50 and ZOE 70 trials in over thirty eight thousand patients showing greater than ninety percent efficacy. This inactive vaccine can be given to patients prior to going on a biologic, prior to going on a JAK inhibitor, can be given while they're on a biologic or while they're on a JAK inhibitor. The downside here is it's cost and it's two injections, and these people have more constitutional manifestation during the or after they get their injection. Pain, redness, swelling, muscle pain, flu like symptoms, shivering, fever, GI upset, up to fifty percent of patients in clinical trials. And you get it the second time around as well.

But it's good news. Now question is, will giving the Shingrix vaccine, this is a subunit vaccine that has an adjuvant, will it make RA worse? Will it make lupus patients worse? Well, that was actually studied at this year's last past ACR with two different studies, one from the University of Tennessee Health Science Center in Memphis, and one from the Brigham and Women's group. The first one was a retrospective study of forty seven patients who received the herpes zoster subunit vaccine.

Most of these were RA, half were on biologics, half were on DMARDs. There were four flare ups overall, not very much and very little in the way of adverse events. No reactivation or shingles events. Mike Weiblak study from the Brigham, a retrospective study of four hundred patients, two thirty six with RA, other diseases also studied. And you can see twelve percent were on TOFAs, twenty six percent on TNF inhibitors.

Flare rate was six percent. This was less than the brass flare rate of thirty percent. The adverse events were mild in most thirteen percent, and then eleven percent with the first dose and eight point seven with the second dose. There were no cases of zoster reported. There is concern, I guess that this could make RA worse.

This doesn't have to be some founded by these two observational retrospective studies. Vaccination is the best way to prevent infection. Let's talk about PCV thirteen and PPSV twenty three, also known as Prevnar thirteen or Pneumovax. This is the sequence on top. If you're one of our patients and you're being vaccinated for the first time, you get the Prevnar first, you wait eight weeks, and then you give the Pneumovax, the PPSV23.

The Pneumovax, as you know, you can give it a second time, but you wait five years. However, if one of your patients got Pneumovax first and that was already given, how long do you wait before you give the Prevnar thirteen? You wait one year. These are guidelines from the ACIP from the CDC. You wait one year and then you give the PCV thirteen.

And then after that you can give PPSV twenty three as long as it's five years after the first time it was given an eight weeks after the PCV thirteen. So the general rules here are first PCV thirteen, wait eight weeks for the PPSV twenty three, the Pneumovax, and again, a second Pneumovax five years after the first. Some general rules as to who should not receive a TNF inhibitor under infectious situations. Number one, those with active hepatitis as demonstrated by a positive hepatitis B surface antigen. You can give it with low risk for people who have a negative hepatitis B surface antigen, but patients who are core antibody positive, they have about a two percent risk of reactivation.

You follow them, you follow their LFTs, you can do viral loads. Number two, patients with a non supercalis mycobacterial infection, NTMs used to be called atypical mycobacteria. These you can find and you can treat but they never resolve. You can find TB, you can treat it but and it resolves and you take your risk back to the baseline risk. Here, they're always at risk, they're never fully eradicated.

The same can be said for number three, invasive fungal infections. I do not mean oral thrush, I mean invasive fungal infections, tissue infections, you can again cannot fully eradicate that. Lastly, patients are getting intravascular BCG for bladder cancer, they have a high risk of activating TB and getting disseminated TB while you're treating them for their bladder cancer. If you'll notice for the first three, there's an asterisk for the number one, number two, and number three. The asterisk means if absolutely necessary, you could use a TNF inhibitor in these situations as long as they're on chronic prophylaxis for the hepatitis B, and that would be like with etanovir, or atypical NTM infections that would be with azithromycin or invasive fungal infection, one of the itraconazole like drugs.

You can do that, you reduce the risk, it doesn't go to zero, but you can reduce the risk. A lot has been talked about thromboembolic events or VTEs and JAK inhibitors. You should know our patients that we treat are at risk. The normal population, the risk is zero to four per 1,000 patient years. RA patients, the rate is about three to six VTEs per 1,000 patient years, it's higher.

And if you give a JAK inhibitor, it's a little bit higher, maybe two or three more cases, if at all possible, not all studies have been positive here. I will talk about that. But recognize this big concern is really an additional two to three events per 1,000 patient years. Let's not get too crazy about this. There's a clear risk of VTE with cancer, RA, ankylosing spondylitis, psoriatic arthritis, all inflammatory diseases.

But again, what is the risk imposed by a JAK? It's not so clear, but it's now a warning. It's a box warning in America and it's even a more serious warning in The EU from the EMA. The first JAK inhibitor developed was ruxolitinib for myelodysplasia. It's not in the package insert, but there are reports of portal vein thrombosis.

Baricitinib, it was in the package insert because of an imbalance of VTE events. Those in the package insert in other countries before it was approved here in The United States. Upadacitinib went on the market with a warning, and at the same time, atopacitinib, which did not have an initial warning in its package, changed when they were doing a long term safety study, which disclosed that patients taking the higher doses of tofacitinib, ten milligrams BID, that was associated with an increased risk of pulmonary embolism and cardiac death when compared to the comparator group taking tNF inhibitors. Now these patients in this safety study were high risk patients taking either five milligrams BID of toposytinib, ten milligrams BID of toposytinib, or adalimumab in standard doses. This has led to a lot of concern and across the board, box warnings for venous thromboembolic events.

And now the EMA has said that, do not use a JAK inhibitor. We're talking about Xeljanz here. But again, it's going to probably in the EMA, it's going to probably bleed over to the other JAK inhibitors. Right now, this is just an EMA guideline for tofacitinib. Xeljanz should be used in caution in all patients who are at risk for blood clots.

The problem is that if you look down here at the third bullet, they say that includes people at a history of blood clots, people who are on hormonal contraceptives receiving hormone replacement therapy, those who are undergoing major surgery or mobile and may also be at risk for people who are elderly, obese, diabetes, hypertension, smoking. My goodness, basically nobody can take a JAK inhibitor. Again, is a little draconian for what I said was an additional two to three events per one thousand patient years. They have come away with a final decision on this. This is only in Europe, this is not in The United States, but I want you to know the more extreme version of this.

How does this play out in practice? If you have a patient on a JAK inhibitor and now you're hearing all this for the first time, do not rush and then you see, oh my goodness, she had a DVT eight years ago or had an MI last year or had a PE in the past. Again, if someone had repeated thrombotic events, I might seriously consider changing the JAK inhibitor. But if someone had one event that was a long ago and they've been on a JAK inhibitor for a while now, more than a year, remember all the bad events happened in the first year, not many years later. Have a discussion with the patient about the risk here.

And is it better to continue the drug that's working versus worrying about the drug that may cause a risk, an additional risk that impacts two or three per one thousand. Think about it. Let's talk about colitis and IL-seventeen inhibitors. You know that there's a lot of trials with ixekizumab and secukinumab that have disclosed this risk. Again, the number of events is very, very low.

If you look on the left, the Crohn's disease risk is about one point one per one thousand patient years. The UC risk is one point nine per one thousand patient years. Again, it's in the warning that you can have the onset of new IBD, ulcerative colitis and or Crohn's disease when taking IL-seventeen inhibitor for the first time. You might want to use caution when giving these drugs to people who have that. Those patients were generally excluded from those clinical trials.

Look at the secukinumab data, it's a little more revealing. Again, the same number of events were seen, but in their psoriasis trials, the CD rate was zero point six per one thousand, that's six per ten thousand. The UC rate was one point four per one thousand. The AS trials, look, it's a little higher. But remember, those old studies in AS where we found that occult terminal ileitis, infectious looking inflammatory disease, maybe incipient Crohn's disease in patients with ankylosing spondylitis and would that come out in time or would that be the basis upon which we would use azolfidine to treat their disease and maybe to treat their risk of future Crohn's disease?

It's not surprising that there's a small, a higher percentage of people here who may go on and develop IBD. So again, I might think twice about using this if someone has a clear cut history of IBD, UC or Crohn's, but I don't worry about it going forward. I certainly don't worry about it if people have a family history. Estimation, that's a crazy kind of stupid. Let's talk about IL-six inhibitors.

These were approved in 2010 for tocilizumab, 2017 for cerilumab. We know these drugs increase lipids, twenty percent of patients will have an increase in lipids. But it doesn't seem from our clinical trials and the long term follow-up, they don't seem to have a higher rate of MACE. But those are in a few thousand patients with these drugs. What happens when you do much larger cohorts out in the real world?

And this is the follow-up studies for cardiac risk. One, there's an INTRACT study with etanercept. This is a large 3,000 patient study that did a head to head comparison of tocilizumab and etanercept in RA patients treated for thirty years. There was no increase in CVDEP or MACE when you were using an IL-six inhibitor compared to TF inhibitors. But tocilizumab had a few more LDL elevations.

They had a few more AEs and serious infections in GI perforations. They're known for GI perforations, the IL-six inhibitors, just like they are with the tofacitinib and JAK inhibitors. Claims data study, over twenty thousand patients followed those on tocilizumab, abatacep, and their cardiac events. The cardiac event risk was equal between tocilizumab and abatacep, no difference there. So again, I think it's important to note that while we worry about that, we worry about that hyperlipidemia.

And by the way, it doesn't seem to be seen in people already have a history of hyperlipidemia and are being treated with a lipid lowering agent. It's already being treated more or less. It seems to be the de novo occurrence here. And some of those patients are going to need to go on treatment and you need to watch that along with the primary care doctor. Overall, the IL-six inhibitors have a very low risk of TB, Hep B reactivation, and preparations, as I said, are seen here a zero point two six per one 100 patient years, zero point one one per 100 patient years comparing tocilizumab and ceruleumumab.

Again, and those rates are about the same as what you would see with a JAK inhibitor. Let's talk about cancer. We have a few more minutes we can go into this. Let's say a patient comes to you with a history of cancer. What drug would you avoid using or I'm sorry, with which cancer would you not use a TNF inhibitor?

A, breast cancer, B, lymphoma, C, cancer, D, skin cancer, E, all the above, F, none of the above. Well, I've asked this question many times to many people and the usual answer is B, and that's the wrong answer according to me, who studied this for many, many years and looked at tens of thousands of patients. The answer is none of the above. None of the above. Your job is to treat the arthritis, let someone else deal with the cancer.

You can worry about cancer and you can refer patients for cancer screening. Patients on TNF inhibitors, the package insert says everyone needs to be screened annually for skin cancer. I know you're not doing it. You should either request it of the primary care doctor or the dermatologist. So what's the overall risk of getting cancer with rheumatoid arthritis?

You can see it's one shown on right. Yes, I are where the standardized incidence ratio is one, but that's misleading because there is a higher risk of lung and lymphoma and maybe melanoma and skin cancers in general. There's a lower risk of colon and breasts and maybe certain head and neck. So the idea here is that it all equally goes out to one. But we do know that there's a lymphoma risk imposed by age, by longstanding RA, and maybe certain therapies.

The question is, do the TNF inhibitors do more than what we see with RA alone or RA severe enough to go on a TNF inhibitor? All this stems from my 2003 FDA hearing, where in the first six thousand patients treated with these three TNF inhibitors, they found six cases of non Hodgkin's lymphoma B cell, non Hodgkin's lymphoma in people on these drugs and none on the placebo. So they did a hearing and they showed a total of twenty three lymphomas. You can see that most of them were not Hodgkin's, and the event rate was three point five to about six point four per one 100 patient years. By the way, this number overlaps the exact number you would have in RA patients.

Many, many population based studies show this is the rate that you see for lymphoma in our RA patients. This study by Bayclin shows that the risk of developing lymphoma in RA is directly related to inflammation. On the top shows low, medium, high inflammatory activity. And look at the odds ratios, one going up to seventy one or functional class disability, one going up to sixty seven. It's inflammation and chronicity that gives you the risk of lymphoma in RA.

You see this in this really good study done in Scandinavia. This is the onset of RA is this line right in the middle. Prior to having RA, the risk of having lymphoma or any cancer was basically one or below. After the onset of RA, you can see there is no real increased risk until you get to after six years. And here, you can see lymphoma risk takes off.

So it's chronicity and inflammation that drives a lymphoma risk, not the drugs. These people were not treated with TNF inhibitors. So there's no good evidence that biologics can cause or worsen solid malignancies. The ACR guidelines say, if you have a solid cancer that's pancreatic, skin, lung, colon, ovarian, uterine, etc, you should treat the patient as if they don't have the cancer, meaning the biologic doesn't affect either their risk or their outcomes. Being on a biologic does not alter cancer mortality, not at all.

There's many studies that have looked at that. It does not increase the risk of cancer recurrence. There's a concern about increasing the risk of melanoma. I'll show you that it doesn't. And I advocate that you treat the arthritis and let someone else screen for and worry about cancer.

This is a Swedish national study, you know, fifteen thousand patients, seven thousand four hundred on biologics. They compared that to forty six thousand on DMARDs and look on the right box, the first invasive, a solid or hematologic malignancy was the same regardless of the drug and compare that to the bottom line, thirteen hundred on a conventional DMARDs and nine fifty on a general population. It's no different with our biologics. Looking at invasive, this is recurrent tumors over here. I'm sorry, these are the hazard ratios for the numbers on top.

It's not increased. What about the issue of melanoma? The concern about melanoma comes from the British Biologics Registry where they showed that patients who were on a TNF inhibitor actually had a lower risk of recurrence of cancer than patients on DMARDs. But for those people who had a history of melanoma and they grouped in people with melanoma in situ and invasive melanoma here, there was a slightly higher risk. This is a study from, I believe it's 11 registries in nine European countries, and the risk of first invasive melanoma with a biologic and they have whole TNF inhibitors here, they've done the analysis with all the biologics, there is no higher risk of melanoma when you go on a biologic with either TNF inhibitor or other drugs.

Again, I'm not afraid to treat anybody with hairy cell leukemia, or lymphoma or melanoma, as I think they need to be treated. And I do not allow my OB GYNs to manage my very sick RA patients, I do not allow my oncologist to manage my RA patients or PSA patients who need to be treated. So the data is very clear. Overall cancer risks, lung, skin, lymphoma, melanoma, breast colon, the risk is the same whether you have rheumatoid arthritis or whether you're rheumatoid arthritis or going on a TNF inhibitor. Same can be said here, by the way, for other diseases too.

So I think it's our job to treat aggressively these things. I'm going to end there and tell you next week, I'm going to be talking to you about the evaluation of febrile rheumatic patients. That's going be Tuesday the fourteenth at 8PM Eastern. I'm going to talk about auto inflammatory diseases and Still's disease and how to diagnose them either clinically or by genetic testing, and what might be your next best therapy. So I'm gonna stop there.

I'm going to give you a brief look at the odds of dying in a house fire is one in one thousand. The odds of a plane crash is one in eight thousand. Dying is one in eleven million. So again, these might be numbers that you want to post. I'm going to post this for you to see on the website in the recording.

So I want you to look for that. Okay, at this point, we're going to go back to each of you. I want to look at your questions and see what we can answer in the next seventeen minutes. So I'm going get a lot of questions about the pandemic. Am I extending the lab monitoring for methotrexate and DMARDs?

No, I'm doing the exact same thing I've always done every three or four months, but I think the question's a good one. I think we tend to do too much monitoring. There are guidelines, think the NICE and the BSRBR, the British registry people came up with a line that said something like for people who you've been monitoring their labs every three months, and in the last eight years you haven't seen any abnormalities with these labs, you can probably extend the monitoring without risk. So that might be a good idea. I probably should adopt that.

How long and when would you do prophylaxis for PCP with Rituxan? I do it in all patients with other autoimmune diseases, lupus, myositis and whatnot. I'm now starting to do it in my patients with RA. I used a lot of rituximab in RA unlike most people. It is a one in thirty thousand risk in RA to develop PML.

It is a one in two thousand risk to develop PML if you have lupus. Again, everybody's losing at lupus. Granted, we may have more choices in RA and less choices in lupus, but I think we should worry about PCP. In spite of my not doing it for many years, I can't say I've seen a PCP in my RA patients on rituximab. Why is the steroids the third approach is still used?

Tony Russell. Hi, Tony. Tony Russell has taught me tons about rheumatology and managing all diseases, including how to use steroids. Why are we still using steroids? That is a really strong point.

Michelle Petrie, if you hear any of her recent lectures, she'll strongly tell you, we shouldn't be using steroids and lupus. You should treat them with steroids, but get them off steroids and manage them more effectively with other drugs. I think the reason to use steroids was that there are a lot of data showing that when steroids are part of a combination regimen, they seem to do better. But I think it's a convention that we can now blow up with all the great therapies we do and knowing the disaster that steroids can cause. I think Tony's point is a really, really good one.

What about IL-seventeen autoimmune hepatitis? I have a PSA patient who has increased LFTs and likely has autoimmune hepatitis. I think your patient has PSA and fatty liver. There is no clear evidence that IL-seventeen inhibitors cause autoimmune hepatitis that I am aware of. Again, I think if you want to make that diagnosis, you're going to either need serologic proof of the diagnosis or biopsy evidence.

Would you keep a patient with colon or prostate cancer on TNF inhibitor? Absolutely. Absolutely. It's my job to treat them. Let someone else treat the prostate cancer.

And let me tell you where you get in trouble. If you happen to live in New York or Buffalo or Houston, where Sloan Kettering, MD Anderson and Roswell Park Cancer Institute are, Dana Farber, there's a whole bunch of them. And you ask those oncologists what to do when they got your patient who's on a biologic. They'll say, you treat them, I'll take care of the cancer and we'll communicate. In the rest of the world where people don't see so much and may not be well versed, you get a lot of advice that says, stop the biologic, stop the methotrexate.

And that's unfounded. And what they're really telling you is people inexperienced are worried about what they don't know. Because to what I said earlier, don't let people know less than you do about your drugs, manage your situation. And yes, an oncologist job is hard and people are crapping out all the time and they have all kinds of toxicities from their chemotherapy. They don't know what your drug is going to do or what it's going do with their drugs.

That's why they want to stop them. If you think your patient really needs it, make sure they stay on it or continue to see you. Here's a good one. What do I do with my RA patient who has active disease and is now due for rituximab infusion? Should I wait?

Well, we dealt with this today in clinic, a patient who is on abatacept and is two weeks overdue on their abatacept infusion. We said right now our infusion centers are being redesigned to accommodate social distancing and hygienic practices to allow for this. Fewer people are coming in for their infusions, so it's not likely they're going to catch that COVID from the contact issue. We're telling the patient go next week and get it done. Rituximab, there's not a lot of data about the downside of being on rituximab and risk of COVID.

So if the patient I would say if the patient has clearly benefited from rituximab, I would give it, especially if it's due. Can you wait another month or two? Can you temporize? Do you want to temporize with steroids which are clearly more dangerous and known to be dangerous in this situation? Go ahead, but I wouldn't do it.

I would give the rituximab. However, the rituximab never worked, then switch, go on to something else. There are a lot of good choices out there. What would you give someone on intravascular BCG? Anything but a TNF inhibitor.

Anything but a TNF inhibitor, I might make my next least likely choice Rituxan and my next least likely choice, a JAK inhibitor. But honestly, would use those. I would use abatacept and DMARDs and I would use IL-six inhibitors without any hesitation at all. Let's see, a patient who has active lymphoma and we were looking to add a biologic, we would favor rituximab and abatacid over TNF. Well, if you're a favorite rituximab, you'll be following ACR guidelines, which are expert consensus.

And I wasn't on that committee, and there's no basis for that recommendation. By the way, there is a registry of RA patients on rituximab and cancers that they've developed. Guess what? They get the same darn cancers that RA patients who go on TNF inhibitors get, which is the same cancers that an RA patient gets. So on the other hand, there's thirty thousand or more patients in clinical trials who have received TNF inhibitors with no added risk of cancer from those observational studies.

I would use a TNF inhibitor if I thought a TNF number was best. I would use the best drug available. Whether it was a TNF inhibitor, abatacept, rituximab, you shouldn't be constrained by any one thing because again, the guidelines aren't particularly smart here. In an RA patient with newly diagnosed cancer, she's undergoing chemotherapy. I think we just answered that.

Have you found that narcotic use increases the risk of infection found with IBD patients on TNF inhibitors? I've seen that data before. I have not seen it in our patient population. I think it says a lot about the patient under study. Patients on narcotics tend to be more complex with more comorbidities.

I think that narcotic is a surrogate for complexity and hence an augmented risk for infection. Have you seen COVID-nineteen in RA patients on biologics? Yes, John. John Goldman from Atlanta has asked that question. I think I addressed that last week in the town hall.

The most recent numbers I'll try to tweak them maybe tomorrow. The most recent town hall I'm sorry, the most recent update to the room COVID registry, the roomcovid.org or the Global Rheumatology Alliance Registry, think they have two twenty patients reported and there's a whole bunch of them on biologics. These are patients who have mostly RA thirty eight percent, forty percent, seventeen percent, sixteen percent with PSA, same number with lupus. I think the number was forty something percent on biologics. Yes, being on biologics doesn't seem to be a factor.

There was a low number of patients who were admitted to ICU in that registry. Right now we need to get more numbers on that. And there's a patient survey going around, which is going be valuable because they'll be able to tell patients who are on hydroxychloroquine or on an IL-six inhibitor and those that are not, and look at what happens to them. Do they get more severe infections or less severe infections, Will they protect or not? We need that data.

And it's rapidly accumulating. If you have a patient who has infection or even suspected infection, add them to the registry. As you heard from Alan Matsumoto last week, it's an easy, easy thing to do. Let's see. Since rituximab can decrease immunoglobulins, is there a particular risk at certain time at this time of COVID?

First off, the data on immunoglobulin levels and rituximab is not what you think. Look at the original data when it first came out. The first two, three, four, five infusions are not associated with a decrease in immunoglobulins. What are you decreasing when you give rituximab? You're decreasing immunoglobulin producing I'm sorry, CD19, CD20 positive B cells.

You are not decreasing plasma cells in tissues that make the immunoglobulin. So you're knocking out the B cells into circulation, not the plasma cells that are doing all the work, which is why the vast majority of patients on rituximab will continue to make rheumatoid factor and CCP and make normal levels of IgG, IgA, IgM. Now, there is the study from Ron Van Boelenhoven, which is the cumulative experience. I think the number is several thousand patients treated for over ten years with a mean of nine infusions. There the number was pretty clear that if patients who had low IgG levels were the RA patients who were at higher risk to get infections before they got and when they went on the rituximab, or those who develop infections after having received rituximab.

So pretreatment IgG levels being low and the same thing or developing IgG levels that are low is a risk factor. Maybe those are the people that might be greatest risk during the COVID-nineteen crisis. I have a patient with COVID-nineteen in the ICU. Oh gee, I'm so sorry, Doctor. Gupta.

The patient has cardiopulmonary sarcoid on Humira approved three weeks ago, methotrexate and prednisone twenty milligrams, we stop methotrexate and the biologic, get the patient off the steroids, lower the steroids, I would have continued the methotrexate, I would have continued the Humira. Humira, there's no reports, by the way, in this COVID era worldwide that the use of TNF inhibitors has been associated with better or worse outcomes. There are reports of patients on steroids and the elderly and those with comorbidity, heart disease, lung disease, diabetes, having worse outcomes, threefold worse outcomes. Now again, the worst outcomes are small percentages. One, two percent now becomes seven percent, fifteen percent becomes thirty three percent or something like that.

But again, these are not universal risk factors, but they do augment risk. I would have kept the patient on those drugs. By the way, I don't know that adalimumab works in someone with cardiopulmonary sarcoid. My impression looking at that data is you do that as a last ditch effort and it's mainly effective in people who have neurosarcoid and ophthalmic sarcoid. But if the patient was responding to their cardiopulmonary sarcoid, then yes, I would maintain that.

I don't think there's a downside to continuing that. My issue with rituximab is that it has a longer half life and it doesn't work. If it doesn't work, I have to wait longer to switch. Well, number one, that's wrong. It's right and it's wrong.

Meaning don't use rituximab as your first choice when you have drugs that you can switch to that have very short half lives and you can make the switch overnight. That includes the JAK inhibitors and IL-six and IL- and TNF inhibitors. You can switch right away. But if someone's not responding to any biologic, including rituximab, you should not be waiting to wash that out. Oh, by the way, they're not doing well, they're failing.

And now you're going to wash them out of a drug that might could be working? Bad idea. They're going get a lot worse and the disease is going to kill them more than a drug. So if I have someone, I've done this many times and Mark Jenebys has a study showing that there's no higher risk of infection. Such patients who are failing everything at a higher risk, like sort of being two percent, three percent, four percent, they might be seven percent, eight percent, nine percent.

But anyway, patients who are failing rituximab, they need something else, move to something else and don't worry about it. Again, that's how you should be doing this prior to the coronavirus crisis. Again, I gave you other reasons, other things to monitor like IgG levels and making that decision. Would there be a COVID concern with abatacep? Not for me.

I don't have any data that would suggest otherwise. Let's see. I might have skipped an infection question from before. Let's see. Thank you.

I think Tammy is making them go away. If a patient gets a URI, what do I do? I do not stop the biologic. If they have the sniffles, I do not stop the biologic. If they have the flu, I do not stop the biologic.

If they have COVID, proven COVID, do not stop the biologic. Stay home, they don't need to be treated with anything. Again, at home coronavirus infected individuals, the ID experts are not recommending hydroxychloroquine. They are not recommending Actemra. Hydroxychloroquine investigational not yet proven, two observational studies suggested not yet proven, there's well designed trials in process.

It is indicated for people who are hospitalized, for people with rapidly progressive advancing lung problems. The use of an IL-six inhibitor is also indicated after patients have had the infection probably for more than a week and you're concerned about their lung disease getting worse from the cytokine storm or them getting systemically worse and they're having high fevers and their CRP levels are sky high. My patient has a CRP level of 500 milligrams per deciliter, 500. And they were waiting for the IL-six levels to come back. What?

They already know what the IL-six levels are going to be. So yes, that patient went on Actemra. I think that was a smart thing to do. Let's see. Patient newly diagnosed with cancer, she's going for chemotherapy, do you still provide DMARDs or do you stop during the treatment?

Nope, I don't stop. Again, the problem is that's what my wish is. If I thought the patient was sick enough to get on a biologic, then I would continue it. I would start a biologic during someone's cancer therapy if their RA was worse or their PSA was worse or the psoriasis was worse. I would start it during pregnancy, especially after the first eight weeks after organogenesis is done.

It's my job to treat the arthritis. I would not stop during treatment. The problem is that when they go to the oncologist and when they go to the obstetrician, now you are invisible with no voice because the person who's driving the bus on treatment decisions is the cancer doctor or the obstetrician and they don't know anything about your disease or your drugs. You could get involved and contact and have an ongoing discussion with those doctors, but again, it's gonna take your effort. I think Doctor.

Abbas says, did I hear you right? Well, turn up your volume and now you can hear me even more right when I say I would not stop a biologic in a COVID positive patient who is now on a biologic. I have no reason to stop it. If they're on an IL-six inhibitor and hydroxychloroquine, great. If not, I'm not going to start it.

But they're on abatacep or an IL-six inhibitor or they receive rituximab, can't stop that. With most of these drugs that you're going to stop, how long is it gonna take to get it out of their system? It's three and a half weeks for etanercept. It's twelve weeks for adalimumab. It's a year for rituximab.

The story is going to be well over by the time the patient has gone through their coronavirus infection. Hopefully they're going to be the eighty five percent who are going to do well and stay at home. If there's a fifteen percent who go in the hospital, then you should be in communication with the doctors in the hospital about how to manage the patient. I'm going to, again, there seems to be a lot of concern about B, I'm more concerned about B cell depletion than you. Well, then I hope that you're measuring B cells, which only tell you half the story.

Because you can measure B cells and they're all supposed to go boom to nothing, right? But you got to measure immunoglobulins if you really want to be worried. And the studies from all the trials show that they have normal immunoglobulins and they blunt their rheumatoid factor and CCP a little bit with many repeated treatments. And I'm talking two infusions two weeks apart, infusion two weeks apart, done every twelve months, I don't do it every six months, that's a failure in my mind. And let's say they're on it for nine years, yeah, after the fifth or sixth time, I'm measuring immunoglobulins.

And I would worry now, as you might worry, if there's a low IgG, the research is pretty clear about that. Rituximab interferes with vaccine responses. You're not giving any vaccines. It interferes with response to neoantigens. This is not a neoantigen.

Elliot, I think that you can't stop it if you don't want to start it, I think that's okay. But it wouldn't change my story in someone who's infected. Right, folks, we're gonna end there because it's the top of the hour. I hope you can tune in next week. We're gonna talk about the assessment and management of fever in our rheumatic patients.

Does that mean it's all inflammatory? Does that mean it stills? And how can I prove one or the other? Thanks for tuning in. Thanks for your questions.

You can follow this lecture, tell your friends about it. We're going to post it on the video section for next Monday, I think. Actually starting probably on Friday, we're going to post this particular video for people to view. We're going to run it for a week. That's it, folks.

Have a good night. Thanks.