QD 68 - Part 4, EULAR RA Treatment Guidelines Save
QD Clinic - Lessons from the literature
Part 4 2020 EULAR Recommendations for the Management of Rheumatoid Arthritis
Adding Biologics or JAK inhibitors
Features Dr Jack Cush
YouTube Link: https://youtu.be/5-1Ah8uyhf0
Transcription
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 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 noninferior, 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, 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, etcetera, 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 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 who have a 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, are you 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 has responded 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 methotrexed flutamide, 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 especially the biologics. But again, 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 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, they 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 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 no longer responding, or if they are non responder 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 ceruleumab may work very well, and there's anecdotal experience about switching between JAK inhibitors. So they're not shutting that down. Obviously, wouldn't 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.
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 noninferior, 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, 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, etcetera, 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 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 who have a 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, are you 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 has responded 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 methotrexed flutamide, 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 especially the biologics. But again, 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 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, they 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 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 no longer responding, or if they are non responder 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 ceruleumab may work very well, and there's anecdotal experience about switching between JAK inhibitors. So they're not shutting that down. Obviously, wouldn't 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.
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