Rheumatoid Arthritis - Guidelines And Para Save

Hello, RNS. My name is Doctor. Jack Cush. I'm a rheumatologist. And today I'm going to talk to you about rheumatoid arthritis, the guidelines, and the paradigms, more specifically, my paradigms.

So enough of looking at me, let's look at my slides. Here we go. So first you should know my disclosures. I do a lot of research and consulting with the companies that have made many of the drugs I'm going to talk about today. Realize that's a potential bias that you need to keep in mind.

Keep in mind also that I do a lot of work with RheumNow. It's, my publication platform. If you're not subscribed to RheumNow, you probably should. I'll send you a daily email that'll look something like this, in that you can see what's happening in the world of rheumatology. That's roomnow.com, sign up.

You'll learn everything about rheumatology and more recently about COVID. So I'm going to talk today about guidelines. And, and I think it's important to consider guidelines when considering the management of rheumatoid arthritis. But you should also consider the fact that guidelines are, problematic. They're hard to do.

Most of the hard questions we have in therapy haven't been answered by well designed clinical trials or studies in drug development. This is a recent report from JAMA Internal Medicine that looked at, the guidelines put forth by the ACR going back to 2010 for, you know, glucocorticoid induced osteoporosis, JIA, RA, PMR, SPA, OA, etcetera. The bottom line is that most of these guidelines are grade C evidence. Grade A evidence, double blind randomized control trials shown there in the A column, you know, only the, you know, the OA had a lot of, grade A evidence. All the other studies are largely grade C evidence, which is guess what?

Expert opinion. And question, who's the experts? My point is, if I wasn't on the committee, there were no real experts on that particular group. Actually, I'm just joking, of course, but there's a subjectivity to certain guidelines, although you can point to them as evidence to get a drug approved or to manage a certain patient. I want to make some comments in general.

First, rheumatologists and, you know, advanced care practitioners who work in rheumatology, I think are exceptional in what they do. You do it because you have great observational skills, you've got a lot of experience. The problem is as great as we are really on paper and outcomes, we're really not that great on a lot of things that we could improve on. We failed to change DMARDs in spite of writing active RA, moderate RA, severe RA in the chart of a patient who will become progressively disabled before your eyes. We talk about treat the target, but nobody really does it, meaning nobody really does a rapid three, a C die, a gas score, whatever, and then makes the decision based on the number on what you're going to treat next.

Nobody does that. We do a lot of repeat serologic assessments and a lot of labs. Think we feel better when we do labs. It's sort of like apple pie and mashed potatoes. It kind of feels good, although it's really bad for you and kind of waste of time.

There's an argument about whether or not we should use poor prognostic factors like high acute phase reactants, seropositivity, especially high rheumatoid factor, high CCPs, not just positive, nodules, erosions, etcetera, in making decisions on aggressive or not aggressive. The ACR stance is it doesn't matter. The UR stance is guess what, it still matters. So I think it's important to have that discussion, when considering, making, how you make your decisions. And lastly, when we don't know what to do, often order labs.

We order a lot of labs, and I think we tend to be weak in how we use labs. Good example, Vectra. Vectra is not a biomarker, not proven to do anything. It doesn't make you smarter. You should already have all the tools you need to make a clinical change.

This is why I wrote a series of blogs and did a series of videos, vlogs on this on my website called The War on RA. I would encourage you to look at it. They'll tell you why rheumatoid arthritis, its management, and where rheumatologists stand today makes me a bit mad, why we need a war on RRA. Next, let's treat RRA. It's easy when you're treating seropositive RRA, but we also treat seronegative RRA, and we treat it exactly the same.

But what is seronegative RRA? Well, in my opinion, it's at least four different things. One palindromic rheumatism, on again, off again, and a third of those people will develop RA, especially the ones who are seropositive. That's a strange little syndrome. Actually, most people present with acute or relatively new symmetric polyarthritis, but are seronegative, we call these undifferentiated, seronegative, undifferentiated polyarthritis, or, it's UPA, USP.

The bottom line is a lot of people with very early disease will be seronegative and more than half of them will remit. So what they really need is some steroids, big blasts of steroids to start, like, you know, I'm Decadron and twenty milligrams a day for two weeks, then ten for two weeks and five. And a lot of them will go into remission. Some, because they have persistence beyond twelve weeks, will need a DMARD, hydroxychloroquine methotrexate sulfasalazine, something simple. And then most of those go into remission.

PMR looks like seronegative from the outset. Yeah, it's girdles, stiffness, and shoulder stuff with AM stiffness that's really bad, and it's in Caucasians, and high severity CRP, but a lot of them will have small joint, medium sized joint, symmetric polyarthritis. They can look just like RA. And then true seronegative RA, which is defined as having a chronic symmetric polyarthritis for at least twelve weeks, more like twenty four weeks, with actual demonstrated palpable synovitis. They meet criteria.

The bottom line is that the longer they carry that diagnosis, the more you should always be asking, what is it really? What is it going to evolve into? You know, I just saw another one the other day that showed up after eight or nine months of seronegative RA, ulcerative colitis is now the diagnosis. That probably was the underlying disorder. Now we got a lot of drugs to choose from in the world of rheumatoid arthritis, especially biologics.

So if you look at, you know, all these, this is 30, just in the world of rheumatology. Let's go down here to RA. You can see, you know, five biologics that are TNF inhibitors. Then three, four, five non TNF other biologics. That gives you a total of nine biologics in RA.

We've got 13 biosimilars that would mimic, and are patterned after infliximab, etanercept, adalimumab, and also rituximab. We got 13 of those. And then add to that approved drugs like the JAK inhibitors, we have three right now, Tofa, Bari, and UPA. And we got one that's gonna be approved later this year, probably, I'm gonna bet that it will be, that's filgotinib, another selective JAK1 inhibitor. And then you got six other drugs you usually use, the oral conventional synthetic DMARDs, hydroxychloroquine, methotrexate, etcetera.

I mean, you've got a lot of choices. That's 25, 31. How are you going to use them? Well, again, I think you can stay within a certain class like the TNF class. You can jump from class to class.

It really needs a strategy. Well, in 2015, the ACR came up with guidelines, which I think are outdated, they're currently revising these. But as these currently exist, it says if you're DMAR naive, and, you have either low disease activity or MDA moderate disease activity or HDA high disease activity, it's basically monotherapy with methotrexate, or if not methotrexate, something else, but monotherapy. If you don't respond after twelve to twenty four weeks, then you go on a combination of DMARDs, right? And that can be, you know, triple DMARD therapy.

That could be a TNF inhibitor. That could be a non TNF biologic. Why are they now allowing, this, when clearly there's a rationale to say use like cheaper, DMARDs, oral DMARDs before you start throwing the expensive biologics or expensive JAK inhibitors? And the reason is these are patterned after the evidence, which is clinical trials showing that there's a lot of drugs that work after you fail methotrexate alone. And that's why TNF is in there with or without methotrexate, why, Actemra and sorrelimab and rituximab will be in there with or without methotrexate, and same thing for now the JAK inhibitors.

Then once you fail those, then you start adding on and going into more biologics or more non TNF biologics. The more recent guidelines come from EULAR. I did a series of videos on this, they're called QD videos. You can look that up if you want me to give you a five minute tutorial. I think I have five of them, twenty five minutes to discuss this.

But here are the, here are the, there were a total of 12 different guidelines they put forth. This was mainly an update of the former guidelines, which is a reiteration from most of them, but there a few new additions. One, DMARC gets started as soon as the diagnosis is made. Two, everybody, the goal is remission or LDA Low Dose Activity State. Three, you monitor these activity every one to three months.

And if after six months they're not responding, that's twenty four weeks you change therapy. I think that's wrong. I think it's like after six weeks change. The convention right now is twelve weeks and then change. But the guideline here says after six months.

Methotrexate, use first. Unless it's contraindicated, use it first because it works best, it's cheap, we know everything about it. It's the anchor drug on most combination drug therapies. It's the best drug we have. If you can't use it, consider leflinamide or sulfasalazine.

They're cheap and they work. Short term glucocorticoids are really important when starting therapy or when changing therapy in the setting of inactive disease, but then you need to aggressively taper and stop it. Chronic steroid use should be discouraged. Next, if you fail the first conventional DMARDs, CS DMARDs, that's like, again, oral methotrexate, in the absence of poor prognostic factors, no nodules, no high erosions, no high CRPs, etcetera, you can use another oral DMART. Whatever.

But on the next guideline says, if they fail one and they do have poor prognostic factors, you need to step up and now add in a biologic or a targeted synthetic. That means a JAK inhibitor or a TNF inhibitor or an IL-six inhibitor. If a biologic DMARD or a TS DMARD, a targeted synthetic DMARD, meaning a JAK inhibitor, is being used, you can combine it with a conventional DMARD like methotrexate, sulfasalazine, leflinamide. That works very well. We know across the board our patients respond best when they're on multiple drugs.

They do say, however, with an IL-six inhibitor, you can be on a methotrexate or not, meaning that IL-six never seemed to have a good track record of working as monotherapy. My opinion and this guideline supports everybody gets combination methotrexate plus a biologic until they're doing great, and then you can withdraw the methotrexate or the conventional DMARC. If they fail a biologic DMARC or a targeted synthetics, use another biologic DMARC or targeted synthetics. And then if you fail one TNF inhibitor, you can either use a second TNF inhibitor, or what's new about this guideline is they said you should maybe consider going to another mechanism of action drug, another MOA, a non TNF biologic, like an IL-six inhibitor, like apatacid, like rituximab. So that's something that you should probably consider.

In the face of persistent remission, they do advocate that you may want to stop or taper the biologic DMART or the targeted synthetic. This is assuming people are largely on a background of a conventional DMART, and they do recommend tapering as opposed to stopping. There's a fairly high amount, at least twenty percent or more of patients who will flare and get worse. The good news is that if you're tapering or stopping, a biologic or target synthetic, and you have to restart, you'll regain control in eighty percent of people. In the face of persistent remission, and again, they're on a biologic with or without a conventional DMARD, you could taper or stop conventional DMARD, although the success of regaining control with that seems to be less effective.

So again, those are the guidelines. I don't know if you live by them or want to. I think we need to go over the paradigms that are real, and I'm gonna give you some paradigm considerations I want you to consider. So the usual paradigm in management is shown on the left. Use methotrexate first.

Some places are forced to use triple DMAR therapy, or methotrexate sulfasalazine plaquenil, or that you must fail two or three DMARs before you get on a biologic. That's the case, why not use a triple DMAR therapy very early, or certainly right after methotrexate? That way you get it out of the way and you can play with whatever drug you want thereafter. You cycle TNF inhibitors, you go from one to the other to the other. It takes twelve weeks to assess whether something's working or not, and often it's much more than that.

The data on that is pretty abysmal. Don't look at it, you'll get depressed. There's data about using the other MOA drugs after the second or third TNF failure, And most people are not using or afraid to use rituximab because of a very rare risk of PML, CNS brain infection. There's a lot of indecision about JAK inhibitor use. Many people are using it early, some people are using it late.

There's no consistency, and everybody's waiting for the big biomarker. That's why fourteen percent of you are using the, Vectra, which is not a biomarker, but you're still using it even though it's expensive and not proven. My paradigm is my way of using methotrexate. That's the next slide. Guess what?

JAKs are better than methotrexate. I'll show you some data. There's a faster time to response, which means you need to make a decision sooner. Consider the other MOA drugs before using a second and third TNF inhibitor. I'm gonna tell you maybe when you should do that.

And then what is difficult RA and how do I approach that? I'm gonna cover that in the rest of the talk. So you use methotrexate, seven and a half, ten milligrams, then you escalate to twenty. I use fifteen or 20 right from the start with my top dose being twenty five. If you have a problem with toxicity, oral toxicity, oral sores, CNS toxicity, the blahs, you tend to split the dose, which is wrong, and you do some goofy things.

The bottom line is that when you use fifteen milligrams or more, you're getting variable absorption when you're giving it orally. If you want 100% absorption, give it I'm or sub q. Sub q is what most people do. I would say on my column over there, at fifteen milligrams, I immediately split the dose orally. Meaning it's not six pills once a week on Wednesday night, it's now three BID on Wednesday.

When you split dose at doses below fifteen, now you get a 100% of absorption. So at fifteen, given as one dose, you might get 40%, 60%, 80% of absorb. If you use it at seven point five twice a day in the same day, once a week, you get 100% absorbed. So at fifteen milligrams and above, it's split dosing same day each week. There's no response.

I will go on to another drug, but I always maintain the methotrexate and add it on. There's good evidence for that. For patients who get oral ulcers or problems with GI problems and diarrhea, vitamin A given every day. If it works well, I don't have time to talk about it, believe me, I know what I'm doing. For patients with CNS manifestations like the blahs, giving more folate's a waste of time.

Going to sub q methotrexate is a waste of time. When you give sub q, you're giving more drug and you get more toxicity, and these features are related to dose. So you could lower the dose for the oral ulcers or for the blahs. For the blas, you give Mucinex DM. It is the dextromethorphan that is protective here.

It blocks NMDA receptor uptake of methotrexate breakdown products. So when someone takes their methotrexate on Wednesday night, they take dextromethorphan, given as Mucinex DM, one pill at the same time, and then they take another pill the next morning. So BID or TID, 12 apart, takes care of 80% of those CNS features. And again, when do you use methotrexate in psoriasis, I think, I don't know, I never used to use it. Now I use it because of the recent data that came out last year, which we don't have time to talk about.

So what about JAK inhibitors? You know, the bottom line is JAKs are better than methotrexate head to head and bileot in methotrexate naive patients. They're better. Most studies, JAKs are better than adalimumab. They've been studied in four studies and they win in most.

JAKs are better than abatacept, the recent study I'll show you. So here's the data that says that JAKs are better than methotrexate. This is the oral START study with tofacitinib. You're looking at purple and blue versus white, white being methotrexate on the left for ACR 20, the middle for ACR 50, and then the time responses over time, it wins big time over methotrexate. And this is in early patients who've never received any therapy.

The same was seen in the SELECT early study, where head to head methotrexate versus, two different doses of upadacitinib. Padacitinib wins seventy, eighty percent, almost eighty percent versus sixty percent with methotrexate for ACR twenty. Why would you not use a JAK inhibitor if you could? And then here, it's head to head against adalimumab, and for the most part, the JAK inhibitors are better than adalimumab, and I circled in all these cases where in fact it was better. And then there are head to head studies.

Now, all rheumatologists, all of you are saying when you're at, the company's asking you, hey, we'd like to see a head to head study. Go, yeah, I'd really like to know how this is versus that, but it really hasn't changed any of your behavior. You're still prescribing whatever it is you're prescribing. You got a cha cha cha little dance you do with your rheumatoid. This is my first drug, my second drug, my third drug.

Don't do that. Everybody's individual here. Head to head, ABBA was better than infliximab in your test study. Head to head, tocilizumab was better than adalimumab in the ADACTA study. Head to head, ABBA and ADA were actually the same.

Head to head, cerdulizumab and adalimumab were the same. The oral SELECT study I showed you that TOFA was better than methotrexate, and then in a study I'm not gonna show you the results of, but it's the SELECT CHOICE study presented at EULAR just two months ago, was surprising that OOPA was better than, abatacep at six months, forty six percent remission versus thirty one percent. But the interesting thing about this study was UPA was better than Avatacep as far as the efficacy outcomes, but Avatacep was safer than UPA, and actually not by a little bit, by a lot. Look on RheumNow to find more about that. Time to response, meaning you start someone on methotrexate or you start someone on a JAK inhibitor, you start someone on, adalimumab, how long do you wait before you move on?

Most of you, if you say twelve weeks, but the studies show it's really more like, you know, forty eight to one hundred weeks. This is the data on a few studies that all say the same thing. Everybody shows significant responses at one or two months. In this study, it's subcutaneous abatacept versus, the IV abatacept. Everybody's getting better, pretty much almost near their plateau level by one and two months.

Here's another study. Head to head, the AMPLE study comparing Avatacep and adalimumab. Look, you see these really important responses, ACR 20 responses, at day twenty nine and day fifty seven. That's one and two months, four and eight weeks. Many studies show that, meaning you should be making your decisions.

You're not looking to get better, you're looking to hit a home run. And if you're hitting a home run, there's going to be evidence of it by week six. My advice is your first follow-up visit should be at week six. If you want to be lazy, or you don't want to change too drastically, make it week eight. And then bite the bullet and make a decision.

Question is, if you fail the TNF inhibitor, do you switch, or do you continue? And that's what most people don't. Do you swap to another mechanism of action or do you continue TNF cycling? Well, before we get into that, I mean, I put this in the wrong spot. This is actually an interesting study from Scandinavia.

Ron Van Vollenhofen presented last year's ACR and this year's EULAR. It's the North Star study. All early RA patients, none have been none were they were treatment naive, and they were either given, usual therapy, which is methotrexate with steroids, that's ACT, or they were given biologic therapy with either sotolizumab, abatacep, or tocilizumab, also with methotrexate. And they looked at how they responded at six months. Look, it doesn't matter.

Everybody responds the same. So if you believe that, you know, etanercept is much better than abatacept, especially early on, you're just kidding yourself, because there's no data for that, because there's no head to head trial. And in all studies that have looked head to head, they all perform pretty much the same. What's really important is what are your rules for starting and then switching, or stopping and switching. That's what's important here.

So you should consider triple DMARD before you start talking about TNF inhibitors and when to switch those. The fact is, most of you don't use triple DMARD, but there's really good evidence that triple DMARD works. That's methotrexate with daily sulfasalazine, weekly methotrexate with daily sulfasalazine and hydroxychloroquine, and it works better or as good as methotrexate plus a TNF inhibitor, studied with, against infliximab and against etanercept. Triple DMARD works in methotrexate incomplete responders and non responders. Again, it's shown to be equivalent to your best therapies.

The true truth is that we don't stay on triple DMARD therapy, MSH, as long as other therapies, but it is a significant cost saving and should be considered. So there's a paucity of trials that prove that TNF switching, going from one TNF inhibitor to another, works. And actually, there's only like two trials that I can really point to. Most of it's controlled observational studies, uncontrolled observational studies from single centers, and that's about it. We tend to dance with the one that brung you.

We love TNF inhibitors. Again, it puts someone on a TNF inhibitor. They want to go bungee jumping and join the marines. They feel fabulous. It's a CNS effect you get with TNF inhibitors that you don't get with other drugs.

And you look good. They love you for this. So you, it's not surprising you can switch to a second one maybe, especially when they work so well for you. The problem is that the other drugs work just as well. And, head to head, other MOAs against TNF inhibitors, they all work the same.

I'm not gonna show you those studies, but there are several of them out there right now. This is the evidence that in fact, that it does work. These are all, open label, a lot of open label studies showing about fifty percent response when you change to a second TNF inhibitor. But most studies show that when you change to a second, drug after a TNF, first TNF inhibitor, golimab and sartolizumab, forty percent responses, the first two lines. Look at the next five lines.

This is what happens when you change to another MOA. You have a 50 to 60% response. Remember, sixtyfortytwenty is the rule. When you start someone on, biologic, and you keep them on methotrexate after they failed methotrexate, you should expect a 60% ACR 20 response. Here, when you change to a second biologic in a TNF network, it goes down to 40%.

Here, when you change to a second biologic but it's another MOA, it's still almost 60%. It's like 50%. This says that when switching other MOAs makes more sense. Consider that. So here's a few studies shows that after you failed a first or second TNF inhibitor and you switch, you either swap and change to another MOA, which is avatarsa, rituximab, or tocilizumab, you do better than if you cycle TNF from first to second.

Okay? And that's looking at overall efficacy, adverse events. I mean, it's a no brainer. Here's another study. The likelihood of being retained on your second biologic is higher when you choose rituximab as opposed to switching to another second TNF inhibitor.

This is an interesting study that, I think is a good rule to live by. And this says, what's your success rate when you start switching drugs? The overall efficacy when you use a biologic is about sixtyfortytwenty. That's what's shown here. That's almost sixtythirty five, sixteen, sixtyfortytwenty.

If you're a primary nonresponder, meaning you didn't respond to your first TNF inhibitor, and you switch to a second or maybe to a third, you drop your ACR20 from 60 down to 47, just like I showed you in the last slide, right? But if you're a secondary non responder, meaning you initially responded to the TNF inhibitor, and now you change, because they lost response over time, changing to a second TNF inhibitor seems to get you a good response, about a sixtyfortytwenty response. So this might be a good situation where a second use would be good, with a secondary non response. Or if you fail for toxicity, same thing. An ACR20 in yellow, a 66 response.

That's good. That's worth doing. But again, if they were an inadequate response, and it's more than two, meaning they failed two TNF inhibitors, and they had an inadequate response, even a secondary response, you do lose ground. So maybe you can change once in the setting of either a toxicity failure or a secondary non response. But after the second one, don't be messing around with TNF inhibitors, move on to other MOAs.

This is the ACCELERATE, a head to head study of cerdulizumab versus adalimumab. And after the first twelve weeks, if you didn't respond to the first TNF inhibitor, whichever one you got, you were switched over to the other one. That would have been a primary non responder shown on the bottom. Look at the primary non response groups. They don't do as well as the primary responder groups, which gets an 80% response.

Primary non responders, 40% response. Again, primary non responder is not a good deal. We're gonna end with a talk about difficult RA. This is all talk unto itself. This is my equation.

Difficult RA is defined as how much damage do you have, times how much disease activity you have, times the number of poor prognostic factors, times the amount of risk that you incur with any particular drug. It's all sort of normalized or divided by how many treatment options you have remaining. And then it's really taken to another degree by, you got it, secondary fibromyalgia. Turns out that bad RA, difficult RA, usually isn't RA, it's a lot of other things. And, these are largely patients who have what I call health traits.

These are people who are noncompliant, won't go, can't do, no shows. They have all kinds of reasons. They ain't doing what you tell them. They are negativistic thinkers. I wrote a blog on this called Diabolical Negativism.

Look at it, it's kind of fun. Poor patient managers. People stink at managing their RA, although it's the disease that may well kill them. Read another blog or hand it to them that says, be the CEO of your own health. Intelligent patients love them, but they can be hell on wheels when it comes to, you know, getting everything right.

I mean, you're the smartest answer to the question, but they want to be equally smart. And that can get in the way sometimes. The people who are magical thinkers, different drummers, the vaccine nuts are sort of a marker for that. God help you if you got one of those. People sleep poorly, have fibromyalgia, people have depression and anxiety.

A lot of recent reports this year showing that people with psychiatric, psychologic comorbidities have poor responses across the board in all of rheumatology. Lastly, how do I manage them? I use the control alt delete. If you're an Apple person, I'm sorry. If you're a PC person, you'll understand.

This is you reboot the system. What does that mean? Number one, control alt delete, delete the drugs that they won't take. I won't take this because it gave me blue toenails. I won't take that because I threw up my guts.

Whatever it is. I don't care what the reason is. It's all it's off the list. Then, next, what else did they fail? You know, anything that they failed, you probably don't want to use that going forward.

And, and that's part of the, the delete group. Next, what, ask them, what controlled you the best of all the drugs that you took? Find a way to use that half dose, regular, a different way of giving it, you know, another modality of giving it, but maybe bring that into the mix and then throw in another drug. And that's the alternative agents. Things that they've never taken before, including anakinra, carambacil, tofa, other JAKs, dapsone.

I've used aprimelast, mycophenolate, glaflinamide, tacrolimus. I don't use minocycline, but you know, when you're stuck, you're stuck. Difficult patients can be difficult. So my paradigm says methotrexate's great. It'll work right out of the gate in at least a third of the patients.

Jacks are better. In the real world where money is in inclusion, if it's my mother and my sister, they're getting a JAK inhibitor before they get methotrexate. Nonetheless, use your best drug first. Algorithms that have you using weak drugs or drugs that you think that you cringe at here, don't use them. You know, fight to use the best drug or best combination first.

You have a a gono go decision at week six or week eight like we talked about. For me, it's one TNF and I'm done. I move on, especially if as a primary non responder. All MOAs are equal to TNF inhibitors. And I use rituximab because it's got the best data as a second biologic.

I'll use all of them. They work great. You get a 10% advantage if you treat people earlier and if you treat seropositive patients with either rituximab, what else, abetacept, and maybe the JAK inhibitors may have a better response in seropositive individuals. I'm going to stop there, and we're going take time for questions. I'm Jack Cush, look for me on roomnow.com.

Take care of yourselves.