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This is QD Clinic. I'm doctor Jack Cush, executive editor of rheumnow.com. QD clinic is brought to you by RheumNow live, March 13 through the fifteenth in Fort Worth. In the next few QD clinics, we're gonna discuss the new EULAR twenty twenty guidelines for the management of rheumatoid arthritis using synthetic and biologic agents. You can download this on the Annals of Rheumatic Disease website.

It's a full read. And I kinda discussed this a little bit last week, but I thought in, you know, reviewing this that there's a lot of detail here, and I think it's worth going over in a few successive videos. So on our first part, we're gonna discuss the overarching principles, how the guidelines were formulated, and and then in subsequent videos, we'll discuss the 12 specific recommendations and then end up with a discussion about where these guidelines are strong and where they are not. So to begin with, this is a current publication. It's in play.

It's got many authors, most of whom are worldwide and mostly centered in the EU. But there is one US author, Ken Saag, representing our interest, here. It's a very impressive group led by Joseph Smolin, Robert Landway, and Johannes Bilsma, and others. They basically, reviewed the history of EULAR guidelines which started out in 2010 for the management RA and were updated in 2016. Along the way, you the ACR and EULAR have collaborated on developing a classification criteria and also remission criteria.

And while their last recommendations were in 2016, they felt that the, advent of new therapies and new data warranted an update in the 2020 recommendations, which had again just been published. As you know, with EULA recommendations, there's always an overarching principles, things to keep in mind, the general approach to the disease or that which is being, promulgated, and then specific recommendations. They have five overarching principles that they, put forth. The first, it's not number one, it's A. It says treatment of patients with RA should aim at the best care and must be based on a shared decision between the patient and rheumatologist.

So, best care makes sense. Shared decision making is something that they've always been in favor of and they believe this is important to get patient buy in, to, improve adherence, and to foster a healthy physician, patient relationship. Inherent in this is a few things. Number one, patient education. This includes an ongoing need for patient education.

If not you, then who in your team will do this? This needs to be addressed. This is vitally important. Patients don't believe in their therapy, they're not gonna use that therapy. And second is the need for communication skills.

You need to be good at communicating RA and its therapy and what it is that you wanna do, and then have that supplemented by others in your team that will help with education. The second principle B is that treatment decisions are based on disease activity, safety issues, and other patient factors such as comorbidities and progression of structural damage. So, they're saying here that, you know, right from the outset you need to consider all these factors when choosing a therapy, meaning there's not one drug that works for all patients, although insurance seems to think so, that you really need to consider how severe the patient is, and what other factors are in play. Patient preferences and patient you know, who come in asking for a specific drug are more likely to respond to that drug than the drug they've never heard of that you're gonna prescribe for them. So their decisions and their wishes probably are very important here.

Comorbidities, we know will color the therapies we use because they will restrict some of the things that we can use and some that we can't use, And that when we get into successive drug failures, comorbidities become a much larger component in choosing therapy, such that you may not have your best or your second best choice. It may be something you have to back into what I call defensive prescribing. So, again, structural damage is also another big issue. You know, so I think all of our drugs, that are on the list here from the biologic to the synthetics really are capable of halting progression. But, you know, you may have a particular view on which does that best.

So these factors are important. Think for instance about the patient who has a history of, herpes zoster or may be at risk for herpes zoster, That people in Southeast Asia are much more greater risk of getting zoster. Same thing for venous thromboembolic events, you may not want to use a JAK inhibitor in someone who recently had a PE or DVT related to RA. The third principle is that room rheumatologists should be primarily responsible for the care of the RA patient. This includes the room specialist nurse, the PA or nurse practitioner that works with the rheumatologist, and also then the multidisciplinary group that is led by the rheumatologist.

The, it's obvious here why the rheumatologist should be at the top of the pyramid when it comes to guiding and treating the patient who has new and problematic rheumatoid arthritis. The fifth, the fourth, entry, D, is that you need access to multiple drugs with different mechanisms of action to address the heterogeneity of RA both from the outset of management and then over the life course of that drug. There are a lot of factors in here, you know, may not always respond to a TNF inhibitor forced upon you by insurance companies, But there may be others that you can't use methotrexate in. So, again, there are things that you can't use from the outset that you'll need choices for. There are choices that you'll need when you have an initial loss of therapy or primary, lack of efficacy.

And then you have it as an issue of patients who are going to lose efficacy over time. And then lastly, you need multiple drugs to manage this disease over its length, which is going to be lifelong in almost ninety percent of patients. And the last, principle e, RA incurs a very high medical and societal cost, all of which should be considered in its management by the treating rheumatologist because you need to address this issue with the payers. You know, the stakeholders that are involved here are numerous, and again, we have to be able to address the issue of, you know, the benefits of one versus the cost of another, meaning that what's the cost of not treating this disease aggressively when it needs aggressive treatment. Well, later down the line, there's going to be incredible cost with regard to surgery, hospital hospitalizations, and complications.

So that's it for this edition, the first edition, overarching principles, regarding the EULAR management recommendations. Tune in for more tomorrow. Oh, come to room now live. Hang out with Artie Cush, Joel Knehmer, Alvin Wells, Roy Fleishman, and a ton of other interesting faculty who will also be at the meeting. This is QD Clinic, and I'm doctor Jack Cush from RheumNow.

QD Clinic is brought to you by RheumNow Live, the little big meeting. Little because you'll be one of a 150 people in the room rubbing elbows with the faculty. It's not like those gigantic meetings where there's 600 people or 15,000 people and you get lost and don't know what to see or do. It's a big meeting because you'll be with big time faculty and have some big time opportunities to exchange meaningfully with them. Also, it's going be big and that's going to be streamed over the Internet to a larger audience.

This week, we're discussing the EULAR guidelines or recommendations for the treatment and management of rheumatoid arthritis. Yesterday, we went over the overarching principles, and today we're gonna start with the 12 recommendations and cover the first three. So number one begins with therapy with DMARN should be started as soon as the diagnosis of rheumatoid arthritis is made. This is sort of a no brainer, but yet there still are a lot of patients who have the diagnosis of RA or are entertaining a diagnosis of RA in whom symptomatic disease management is occurring. If I make a diagnosis of rheumatoid arthritis or have a strong suspicion and I'm going to order confirmatory labs, the patient leaves the prescription, leaves the office with a prescription for methotrexate or another real DMARD, and that may be tailored up to maybe multiple therapies.

Again, can always stop them at any point. The gravest mistake in managing RA is to not be aggressive, not diagnose early, not institute treatment early. I kind of like my EMR for the one simple fact that if I have a diagnosable RA and the patient isn't on a DMARD, my EMR is asking me why is the patient not on a DMARD. And I think that that sort of makes sense. You don't wait, you don't sort of wishy wash about, well, let me just see how they respond to nonsteroidals or low dose prednisone or let me use some hydroxychloroquine because I really can't make up my mind here about whether this is or isn't rheumatoid arthritis.

Either you're in or you're out. Either symptomatically management and call it undiagnosed inflammatory arthritis. But once you put a label of RA, m o five dot seven nine or m o six point one or o nine for seronegative, you need to start DMARD therapy. Again, to not to to have RA and not be on a DMARD is to not have RA. Recommendation number two, treatment should be aimed at reaching a target of sustained remission or a low disease activity state in every patient.

This is a carryover from the twenty sixteen recommendations. It makes a great deal of sense. I think you want, obviously, to have a t to t attitude. Treat to target is strongly advocated in, by EULAR. They have recommendations on on treat to target and its benefits.

I think that it doesn't matter what target you're going to use or what tool you're going to use. You need to use the tool and treat to that tool. So, again, ACR guidelines with Euler, I think, said that C dye is preferable, but it could be SDI, it could be rapid three. I use a gas score, which is patient pain, HAC score, and, their pain level. Pain, HAC score, and tender joint count, it actually turns out to perform just as well as the CDAI score, which is probably the best correlated with the dash 28 ESR.

Nonetheless, it doesn't matter which one you use. A goal of, in the case of CDAI or gas, of LDAS, loaders activity state of seven or less, or remission of three or less is what you need to have. If you don't get there, then you need to move on. The question here are the time frames. The time frames are actually, critical.

They say here that if you're not getting there let's see now. If you're not getting there within what's the next guideline? So, again, use the the these treatment guidelines to get the best response, use the tools that you have, these validated tools on assessment to achieve your target. Now, should be going for remission, but sometimes a low disease activity state is prudent, and that would be patients who already have, damage, where because of their damage, because of secondary degenerative change or periarticular disease, you may not get to a very low score, but you may get to a low enough score to indicate that they're in a low disease activity state. The third and last one we'll consider today is monitoring should be frequent in active disease, meaning every one to three months.

If there is no improvement by month three, after the start of treatment, you need to be changing your treatment. Or if you don't achieve your target, let's say a C. Dye of less than three, by six months treatment should be changed, adjusted, whatever you need to achieve your goals. So they're putting a twelve week limit on the attainment of improvement, and they define improvement as at least 50% improvement in TJC and SJC. I think these are a little too lax.

I think with many of the drugs we have now, you should be getting better in two weeks or four weeks. So and I would say six weeks is really where you need to make be making changes, but that's the Jack Cush recommendation on management, not the ULAW recommendation. They do go on to point out that rapid attainment of a selected target endpoint is now regarded as being the most critical of of sensibilities you need to employ here. There is evidence that says that if you don't achieve this rapidly, that if you don't achieve at least a 50% reduction within three months, the probability of reaching the treatment goal of remission is low. So, you do need a rapid response.

Rapid responders are people who are gonna have fantastic responses to the drug you're using. If you're getting a so so slow response, takes twelve weeks, sixteen weeks, maybe twenty four weeks to get to the goal, well, how good is that therapy gonna be in the long run? Again, I think you really need to think about that. These guidelines are being laid out in sequence, in in accord with the idea of starting out with someone with early RA and new changes to therapy. It conforms the algorithm that they use and is on the website and in the paper.

That's it for episode number two of UR recommendations regarding the management of rheumatoid arthritis. QD clinic is brought to you by RheumNow Live. RheumNow Live where the audience matters. Did you know that at RoomNow live, we have sixteen hours of CME, and nearly five hours of that sixteen hours is devoted specifically to q and a between the audience and the panel, the panel being the faculty in each of the sessions we're going to have on the various disorders, rheumatoid, we have two on rheumatoid, psoriatic arthritis, ankylosing spondylitis, lupus, etcetera. So, again, be part of the audience.

I think you'll enjoy it. In this edition, we're going to talk about, again, EULAR twenty twenty recommendations on the management of rheumatoid arthritis. This is part three in a series where we're going to review the specific recommendations. Yesterday, we reviewed recommendations one through three, and now today, we're gonna review four through eight. But first, before we do that, recognize that in considering your treatment options, the UR guidelines will point to something called poor prognostic factors.

And is this an issue when you're managing your patients with rheumatoid arthritis? Many of you would say yes. What are poor prognostic factors? There's a number of them that's been previously defined, but includes persistence of disease activity despite therapy. Second, high, usually very high elevations of sed rate and or CRP.

Next is a sustained high swollen joint count. Third is high titers. Fourth is high titers of rheumatoid factor and high titers of CCP antibodies. The presence of erosions obviously, is an important factor. And then lastly, failure of two or more disease modifying therapies.

Any combination of these would constitute someone who has a poor prognostic factors or list of factors that will weigh on the outcome and may require more aggressive therapy. So let's get into the fourth recommendation on the, document provided by the Annals Rheumatoid Disease. Number four, methotrexate should be part of the first treatment strategy. This was in the prior guideline. Obviously, methotrexate first.

It's methotrexate or die. If someone has RA, they need to be on methotrexate unless there's a strong contraindication. Why? It's our best drug. We have a tremendous amount of experience with this drug.

We know what it will do. We know how long it takes. We know how to dose it. It is not just the first drug to start, it's the anchor drug upon which you build other therapies going forward. Someone doesn't respond to methotrexate, you're gonna add on turns out, if you take methotrexate away and just add on another therapy without methotrexate, they don't do as well as keeping them on methotrexate.

Yes, that's the drug that they didn't respond to. So it's the anchor drug whether you're going to add on glucocorticoids, a conventional DMARD, a biologic DMARD, or a synthetic, targeted synthetic DMARD. Again, what's the dose? I start at fifteen milligrams. Some people still start at ten or seven point five.

Recommendations say the goal is to get to point three milligrams per kilogram, and that you should escalate the doses every four to six weeks trying to get to a target dose. In The US and and the and the EU, that's generally a dose of twenty to twenty five milligrams per week. In Southeast Asia, it's a lot less, being around ten milligrams or a little bit more. Obviously, starting methotrexate mandates that everyone should be on folic acid. Folic acid has been proven to, number one, reduce the amount of discontinuations.

Number two, reduce the amount of LFT elevations. And number three, no. It doesn't lower oral ulcers and nausea, but and again, that's how everybody uses it. How you use folic acid or folinic acid is up to you. There are many regimens.

They all work. And lastly, because methotrexate is so important, and because patients will read about it and think it's a cancer drug, patient education is very important. I love to say that methotrexate is a drug that we love and that patients hate because of what they read and what they're worried about. A few caveats on methotrexate. When you're gonna be at fifteen milligrams or above, you either need to switch from PO to sub q, or what I do is go to split oral dosing.

So at fifteen milligrams or higher, oral dosing has variable, absorption. But if you keep that at seven and a half to ten milligrams and then do it bid on when every Wednesday, get you almost a 100% absorption just as you would if you went to a parenteral administration. Second, the things that screw up the use of methotrexate by patients are two key features. One, oral ulcers, queasiness, GI manifestations. The treatment there is vitamin A.

Eight thousand units a day, it works incredibly well. Stop me and ask me about it, I'll tell you about it. Second, the methotrexate blas. Taking methotrexate in the next day or thirty six hours they have the blas. CNS fatigue, can't get out of bed, don't feel like doing anything, again that's treated by taking with the methotrexate dextromethorphan.

It produces a competitive, inhibition of binding of methotrexate metabolites, excitogenic amines, to NMDA receptors in the brain. It prevents this methotrexate blase and other neurologic, and constitutional manifestations that follow methotrexate for thirty six hours. You can take it with the methotrexate dose, and then maybe the next day once or twice. I I I use Mucinex DM. It's got thirty or fifty milligrams of DM in it.

It works really, really well. Why not recommend a biologic since that's everyone thinks that's our best therapies? Well, studies have actually not shown that. Head to head against methotrexate in brand new patients, biologic DMARDs do not perform better, and obviously they're a lot more expensive. The question is whether or not you should use an early biologic or a late biologic.

That was actually in this week's room now. The VEDERA study, by Paul Emry's group showed there was no advantage to using very early, etanercept when starting methotrexate in early RA patients, and that the responses were basically the same as if you waited until they didn't respond for twenty four weeks and then added on, and patients quickly do catch up. That's item number four on the recommendation. Item number five reads as follows. If patients with contraindications methotrexate or early intolerance occurs, you should be using leflinamide or sulfasalazine as your next best first treatment strategy.

They perform equally well in head to head trials, certainly methotrexate and and leflinamide. Sulphazalazine, maybe not so much, but then again it's in the same bracket. Worldwide, leflinamide gets a tremendous amount of use because it's often the preferred drug to biologics and as opposed to North America where we use more biologics as second line. Plaquenil didn't make the list. Hydroxychloroquine in that article said that it has a limited place in the management of RA, especially early on, and mainly in its use in mild RA.

Clinical trials, done a long time ago continue to show or have shown that it is clinically weak as far as efficacy, but has no evidence of structural benefit as far as structural structural efficacy. So hydroxychloroquine is an add on drug, not your first line drug. Item number six, short term glucocorticoid should be considered when initiating or changing a conventional DMARD in different dose regimens and routes of administration, but should be tapered as rapidly and as clinically feasible as possible. Basically what they're saying here is it's bridging therapy while you're waiting for the DMARD to take effect, you know, your fastest effects are probably with the JAK inhibitors, your slowest effects are going to be with sulfasalazine, Plaquenil, and Rituximab. Everything else is, you know, six to eight to twelve weeks.

Maybe you need steroids during that period to get them over the hump. They didn't specifically say who shouldn't get steroids at the outset. They said they were kind of liberal in saying that everybody should get them when you're starting therapy. And I think you need to keep in mind the short term benefit of glucocorticoids, but the long term hazards and risk. Again, steroids are acutely wonderful and chronically dangerous is what I tell my patients.

Item number seven, if the treatment target is not achieved with the first conventional DMARDs, methotrexate, leflinamide, etc, in the absence of poor prognostic factors, other conventional DMARDs should be considered. This was in the 2016 recommendation and is carried forward. What they're saying is that in the absence of poor prognostic factors, you can continue to use conventional DMARR therapy or combinations of conventional DMARDs as opposed to jumping into more expensive, more aggressive therapy with either biologics or targeted synthetics. So that's a very important, factor. It doesn't matter whether you switch to a conventional DMARDs or add on conventional DMARDs.

Makes sense to add on if you ask me. But again, that's really your choice that to be made with the patient. Item number eight, our last item for today is if a treatment target is not achieved with the first conventional DMARR therapy and poor prognostic factors are present, remember, erosion, CRP, many swollen joints, high titers, rheumatoid factor, o, then a biologic DMARD or a a targeted synthetic DMARD should be added. And, again, not replaced, but should be added. I think these are all important factors.

And, again, what's different about this from the 2,016 recommendations that said before that maybe you should use a TNF inhibitor first and then after that, a targeted synthetic. Here, looking at the data, there is no particular advantage. In fact, there are studies of JAK inhibitors outperforming not just methotrexate, but outperforming, TNF inhibitors mainly adalimumab in sort of head to head fashion with a background of methotrexate suggesting that it doesn't matter whether you use a TNF inhibitor or JAK inhibitor, or other targeted synthetics. Right now, we only have JAKs, at this point. So it's either or.

And, again, they they didn't say consider. They say add. Like, make the change, buddy. It's time to put up and and and make the patient get better right quick. In tomorrow's episode, we're gonna talk about the toxicities that we need to consider before we go on to other traits other treatments in patients with advanced disease or advanced therapeutics.

Tune in for more on QD clinic. Welcome to QD clinic brought to you by Room Now Live. Room Now Live is a master class for the next generation of rheumatologists. In this episode, we're gonna do part four of our discussion on the 2,020 EULAR recommendations for the treatment of rheumatoid arthritis. I wanna end up with an addendum to item number eight, recommendation number eight.

A few things. One, adding a biologic also means adding a biosimilar. If it's an approved biosimilar, it's the same as adding the original biologic, and that's advocated in this document. I also advocate for that as well. Again, they talk a little bit about the JAK inhibitors because that's brought up now under targeted synthetic DMARDs.

They're really talking about the JAKs, and there are numerous JAKs in development. JAKs have looked very good. Head to head, they outperform methotrexate. Head to head, they sometimes outperform TNF inhibitors, mainly adalimumab. That was shown for baricitinib and upa or padicitinib.

The JAK inhibitors were shown to be non inferior, meaning roughly equal to, the JAK when or the TNF inhibitor when, in the tofacitinib trials and also in a recent filgotinib trial. We're waiting on data for pefacitinib, a fifth JAK inhibitor, not yet approved filgotinib, not yet approved, and there's still trials going on in those two drugs. So, again, JAKs are taking on bigger roles and and may be used earlier in some places, but there still are restrictions by formulary, by cost. And there are two other issues. One is that of zoster.

Certainly, patients in Southeast Asia, both China and Japan, have a higher risk of herpes zoster and shingles, and hence maybe those should not be frontline therapies, not first line therapy, maybe not even second line, where again the risk, I'll give you the relative risk in a second, But it's important to know those risks. It is augmented. It's maybe as much as three to fourfold higher than what you might see in an RA patient on a TNF inhibitor. The other issue with the JAK inhibitors that could curtail its use is that of venous thromboembolic events, VTEs, first brought up became a highlight issue for baricitinib where it got a boxed warning. It was not a warning for any of the other, for the only other JAK inhibitor out at the time, which was tofacitinib, but that's all changed.

Now all the all three JAK inhibitors in The US have a box warning largely because it's been seen with all the JAK inhibitors and also because tofacitinib had a very large post marketing study in high risk individuals with cardiovascular risk, cancer risk, etc, and they gave them either five milligrams BID or ten milligrams BID. Three years into the study, they note, their safety committee notes, that there's a higher rate of VTEs and and and cardiac deaths in patients who are taking ten milligram BID or high dose of tofacitinib, a dose that's only approved for use with, ulcerative colitis. So this has set off a storm of discussion, especially at the EMA more so than even the FDA, where they haven't come about with their final recommendations, but the EMA has had some major concerns about this. And this document, this guidelines document says that, you may not want to use a JAK inhibitor in patients over prior history of venous thromboembolic events. Makes sense.

Right? If you're not yet on the drug, choose one of the other drugs if they already had a PE or DVT. But they go so far as to say that you may have a higher risk if you're someone if your patient is obese or is on hormone replacement therapy or if they're very old. Should those be absolute contraindications to the use of a JAK inhibitor? I say not, and it's not actually a guideline from either the FDA or the EMA, although the EMA was talking about going this way.

We'll have to wait and see what they do. But, again, I think this is important to understand the numbers here. The, population risk is about three per one thousand for a VTE event. An RA patient's like three to six per one thousand. When the RA patient goes on a JAK inhibitor and it's been elevated, sometimes even with other drugs, we're talking about event rates of like six, seven, eight per one thousand.

We're talking about a two per one thousand, maybe three per one thousand increased risk imposed maybe by the drug. We know RA patients are at a higher risk. So on that basis, you're gonna stop someone who's taking a JAK inhibitor who's doing really well. I don't think that's a good idea. Are you gonna avoid using this drug at all costs?

Maybe not if they're obese or on hormone replacement therapy. Again, you're gonna have to discuss these issues with the patient, but be aware of what's in the guidelines document that we're talking about here. So, anyway, I think that's very important. We're gonna move on to items number, nine and ten. The recommendations number nine says biologic DMARDs and TSDMARDs, targeted synthetic DMARDs, should be combined with a conventional DMARDs in patients who can, overall.

So if patient does respond to conventional DMARD, you add on the biologic or the the the targeted synthetic. However, in patients in whom you cannot use a conventional DMARD like methotrexate, then there may be some advantages to using IL-six inhibitors, and JAK inhibitors, targeted synthetics. And that's largely because that's what the clinical trials have shown. So you do want to add on therapy, the biologic or the targeted synthetic, to a conventional DMARC because there are clear cut benefits. There are benefits as far as x-ray, as far as efficacy, and also as far as immunogenicity for the especially the biologics.

But again, there are situations where maybe, you can't do that. They acknowledge that there are clinical trials showing atosolizumab and the other IL-six inhibitor, ceruleumab, have been shown to be effective, equally effective as monotherapy as have the JAK inhibitors. So there are selected instances where monotherapy is permissible and shown to be reasonable based on the data, and those are the drugs that they point to. Item number 10. If a biologic DMARD or targeted synthetic DMARD has failed, treatment with another biologic DMARD or a targeted synthetic should be considered.

Specifically, say if a TNF if the first TNF inhibitor therapy failed, patients may receive an agent with another MOA or a second TNF inhibitor. This is the departure from prior guidelines where they said you could use one or the other, didn't really matter. Here, they've gone so far as to say, you should use first another MOA and then or maybe a second TNF inhibitor. And then in their language, they kinda get a little wishy washy saying, it looks like other MOAs are the better way to go. Other MOAs being abetacit, IL-six inhibitors, rituximab or B cell inhibitors.

Because in studies it looks that way, especially for rituximab. But a lot of those studies are not really well designed and to really specifically answer this question. So they kind of say a second TNF inhibitor would also be effective. But they want to put out there, there's plenty of mounting evidence, growing evidence that other MOA may be the way to go after failure of the first TNF inhibitors. What are my rules in this situation?

Number one, if you had a primary failure of your first TNF inhibitor, do not use a second one. The data is very clear. You'll lose a lot of efficacy points by going with a second TNF inhibitor, whereas you do great if you use another MOA drug. However, if you fail the TNF inhibitor for secondary loss of efficacy, meaning after six months or more they're no longer responding, Or if they are nonresponder because of toxicity, it may be prudent to use a second TNF inhibitor. However, it's not prudent to use a third one.

Sorry. Don't do it. It's a bad idea. Clinical trials, in these situations have shown other MOAs are far more preferable. Also, under this section, they talk about should you be doing switching, like we're talking about switching from one TNF inhibitor to another.

What about should you be switching from one JAK inhibitor to another or from one IL-six inhibitor to another? There is some preliminary data that suggests that switching from tocilizumab to cerulimab may work very well. And there's anecdotal experience about switching between JAK inhibitors. So they're not shutting that down. Obviously you would want to keep switching between three or four JAK inhibitors, but to go from one to the other may be a reasonable choice, especially in patients again who have failed a combination of a conventional DMARD with a biologic or targeted synthetic, you can switch again amongst those or switch to another MOA.

Anyway, that's it for edition four. In our last edition, we'll talk about the final two recommendations about what to do in people who are doing great. Can you withdraw therapy? Lessen therapy? Stop therapy?

And then what are some of the weaknesses, and considerations you need to think about when using these guidelines to manage your patients with rheumatoid arthritis? Check out roomnow.live and register. This is QD Video, and I'm doctor Jack Cush. QD Video is brought to you by roomnow.live. This is our fifth installment, final installment on our discussion regarding the 2,020 EULAR management guidelines for rheumatoid arthritis.

We previously discovered the five overarching principles, discussed the first nine items or 10 items actually in a 12 item and recommendation. And today, we're gonna finish up with two more. Number 11 says, if a patient is in persistent remission after having tapered glucocorticoids, one can consider tapering biologic DMARDs or targeted synthetic DMARDs, especially if the patient if the treatment is combined with a conventional DMARD, meaning the patient's on a background DMARD in addition to the so if patient's on a conventional DMARD and a biologic or a targeted synthetic JAK inhibitor, which one would you target if someone is in persistent remission? I think it's important here to note a few things. They're saying first that you have to be in persistent remission.

Rheumatoid remission, not LDA. Second, they talk about tapering, not discontinuing. These guidelines are kind of against discontinuing because if you discontinue drug, even in patients who are doing great, the chance of long term success is probably around ten to fifteen percent based on prior studies. So they're talking about tapering. That means dose reduction or interval increase, and that's an important distinction.

This particular item, item 11, says that if you're on a conventional DMARD and then an expensive drug in addition in combination and you achieve remission off of glucocorticoids, then you would stop the expensive therapy, the biologic or the targeted synthetic or JAK inhibitor. And the question is, is that the right choice or should it be the cheaper drug, the conventional DMARD? Again, that's dealt with it actually actually in item 12. So what does it mean to achieve a target? Here, they are largely talking about persistent remission, and there is no firm definition of persistent remission.

It could be six months in or twelve months of achieving remission by a DAS or CDI or Rapid three score, but again the longer the better. Many of the studies that have been that have done that have researched this issue with different regimens have looked at patients in remission for six or twelve months and showed that it does work sometimes with some stipulations, which I guess we'll go over. So it can't be just low disease activity and doing well or well enough. They really talk to remission. What I say in my clinic is, and a patient asks, doc, when can I go off these medicines?

I say, RA is a lifelong disease and it's not likely you're gonna get off therapy. Chance of going into drug free remission are only ten percent. Let's try to get to remission and then we'll have that discussion. Let's you show me one year of remission and then we'll lessen your therapies. You show me two years, well, maybe even less less than more.

So I think twelve months is probably the right number. Again, I want to remind you of the ACR guidelines on this, the 2015 I think guidelines, which basically said if you're an LDA, low dose activity, you don't change therapy. But if you're in remission, you could stop one or less than one, but not both. So what we do know is that if you try to go off therapy completely, there's a high flare rate. The good news that the authors say here is that the consequences of flares are minimized if you're stopping the targeted synthetic or the biologic because you can recapture disease control in over eighty percent of patients with those drugs.

However, if you stop the conventional DMARD, you don't recapture control as well, less than fifty about fifty percent can will revert back to where they once were. So, I think that, again, it makes great sense to be in in persistent remission and then there's this argument about deep remission. There are research studies showing that patients who have a DAS score of like 2.1 or less are more likely to stay in remission and not have flares. So, again, there are consequences to stopping or therapy, there are consequences to lessening therapy. We do know that, again, the main consequence is flares.

The question is, will there be, with flares, a consequence as far as radiographic progression or long term disability? That's really unknown and not been studied. Item number 12, what does that say? Well, it says, if a patient is in persistent remission, tapering the conventional biologic conventional DMARD should be considered. They want to consider that separately because, again, you have to weigh which is the more prudent choice.

Is it going to be the drug the patient likes the most that they stay on or the drug that they hate the most that they go off of? Is it going to be the most expensive drug that you stop? Is it going to be, the drug that gave the most persistent or most impressive response when it was added to the regimen. These all have to go in, and it is not unreasonable to taper the conventional DMARD in patients who are on a combination and in remission. Persistent remission, even better, deep remission, if you can find that and if you know what that is.

So what are the downsides to these European these European EULAR guidelines? There are but a few. And first off, how do they differ from the ACR guidelines? Note that the ACR is actually in the process of updating its guidelines, which I think came out in 2015. The ACR guidelines do not, make use of poor prognostic indicators in choosing the level of therapy, whereas the UR guidelines do.

The ACR guidelines are all about how severe the disease activity is when it comes to choosing therapy. Neither of them talk about what to do in preclinical RA patients who may be at risk because of a first degree relative, and they are seropositive and now they have arthralgias. A lot is not known about that. There are recent papers out there including one by Paul Emory and others that are looking and commenting on this. Again, I don't start DMARR therapy on these patients unless I have synovitis.

There's no real depth here on switching within a class. If you fail a JAK inhibitor, can you go to another JAK inhibitor? If you fail an IL six inhibitor, can you go to another IL six inhibitor? They did address the issue of failing a TNF inhibitor and whether you go to a second one or another MOA. They came around just blanketly a priori saying it's probably better to go to another MOA than to go to a second TNF inhibitor, but we talked about that, I think, in part four of this series.

They really don't give you a lot on when monotherapy is prudent. They sort of talked about it in terms of, well, if you can't use combinations of drugs or whatever, then maybe a JAK inhibitor or an IL-six inhibitor may be the better choice. But I think a better definition of who should be getting monotherapy. Drug companies want to tout their monotherapy data because it distinguishes them from all other drugs. We know patients do best when they're given a combination of drugs because we really can't predict who's going to do great on one drug.

Let time tell that. There's no indication or no study that actually says that really well. They don't have much in the way about how safety factors into this. I call that defensive prescribing. It's sort of a secondary, tertiary, quaternary decision making tool when because the patient has this, then you do that.

So I think we need better guidelines on if this, then that management of RA. So what do you do in the in someone who's had a deep tissue fungal infection in the past? I had a patient with coccidioidomycosis that I saw today, that's coloring the treatments that she can take. Again, I think it's a much larger discussion that's probably why it's not in these guidelines. And lastly, maybe the biggest challenge we have in managing our patients is that of adherence to therapy and non compliance with therapy, not even filling the prescription that you prescribe for the disease that you know is going to maim them if not kill them.

So, again, we need to have better strategies and a better understanding on how we can better address the needs of our patients by sort of safeguarding against the temptation to look at wacky internet sites and natural therapies or something sold by cousin Alfie out of the back of his car which seems so much more appealing than that biologic that has a one in thirty thousand risk of PML. Again, there's a lot of reasons why patients don't follow through on your instructions. We need to have strategies to better deal with that. I hope you found this review interesting and helpful. I found it interesting to review.

Tune in next week for more QD clinic. And by the way, RheumNow live. You know, let me close with something about that. I think it's kind of a cool thing to be involved in someone else's great project or a great dream or incredible vision. Artie Cavanaugh and I, when we sat down and dreamed up RheumNow live, we wanted a meeting where people are gonna be connected, where they're gonna be highly engaged, not only with the other audience members, but also mainly with the faculty when there was gonna be a high degree of interactivity, and that we're gonna be Internet based, and that we could not only just do it within the room, which was gonna be fabulous, but outside of the room.

We have these TED talks, we call them step talks, that are intermingled throughout the the the program that are just tremendous. Short, wham bam, you know you know, sort of groundbreaking kind of new thinking on things that you've heard about or you'd like to know more about. Anyway, a lot's happening. Go to rheumnow.live to check out the program and to register. Next week.