Difficult to Treat RA Save
Transcription
This is advanced practice rheumatology. In this review, we're going to discuss difficult to treat RA, also called D2T or refractory RA. We'll go over the definition of D2T as established by EULAR. But I want to throw in some other scenarios of RA management that I would call difficult to treat and should be considered as such because if these occur, you're more likely to be meeting the definition of difficult to treat down the line. Specifically, I'm talking about recurrent rheumatoid arthritis flares. I'm talking about seronegative rheumatoid arthritis and I'm talking about complications of RA especially interstitial lung disease associated with RA.
So first let's talk about flares in RA. They're common. They happen 30 to 60% of patients. And there are many studies that show this happens most frequently when you start to withdraw therapy. I don't know why we do this. I don't do this. You spend a lot of time, effort with trial and error trying to find the right drug and combination of drugs to control a chronic systemic inflammatory disorder that has deadly complications. And then once you achieve a great response, the patient and you want to stop therapy. I don't think that's a really good idea at all.
So these occur frequently. They're going to occur if you taper DMARD or biologic therapy. They're definitely going to occur if you stop DMARD or biologic therapy. And there are significant consequences to these flares. One flare not so bad. You can manage it with temporary medicines, but repeated flares will have worse 12-month outcomes in the things that matter most to the patient. Surprisingly, there will be more X-ray progression with repeated flares and a higher cardiovascular risk. And lastly, there are certainly economic consequences to flares with being out of work, more health care utilization, more comorbidity management.
How do you manage flares? The best way to manage flares is to avoid a flare. Keep them well controlled. Keep them on stable therapy. The goal is to be boring and stable. This is working. Let's not change a thing. Just follow them. Don't taper. Don't stop DMARDs or biologics. The goal is remission or low disease activity state in some.
Secondly, I think you should be documenting the flares. Often patients will call and say, "I'm flaring," and they'll be managed over the phone without ever being seen or without any kind of metric being used to document the flare. You can use remote assessment tools or telemedicine or surveys over the phone to come up with a RAPID3 score, a PAS score. There are other things that you could do, or you could bring them in and do a joint count and a CRP, or whatever it is that you like to follow in your clinic.
The treatments for flares are thankfully simple, cheap, and effective, but they do have toxicities. The problem is they're really not that effective. And often, I think it's time and rest that will be more effective for most flares. But we'll talk about management of D2T RA and how that impacts outcomes.
But for a flare, what are your choices? Analgesics, acetaminophen, tramadol, weak narcotics, non-steroidals. You know, these have been largely shown to not work or have minimal effect, but only impose risk. I do use a fair amount of extended-release acetaminophen. I think most people don't use acetaminophen correctly, meaning they're using short-acting 325–500 milligram acetaminophen and not the long-acting acetaminophen of 650 milligrams. I will up their dose to two to three pills twice a day during flares. With or without a non-steroidal in low dose, with or without a low dose of steroids, but you worry about toxicity, do you not? Especially with non-steroidals, for people who shouldn't be taking non-steroidals.
You always recommend rest, you know, cutting back on activities, cutting back on exercise, stop doing the thing that caused the flare. Those would be smart. And then steroids. Everybody's got a game they play with steroids. You know, come in for a steroid shot or take a Medrol dose pack or, you know, take 10 milligrams a day for 3 days or start out with 15 milligrams a day for 2 days, 10 milligrams a day for 3 days, 5 milligrams a day for four, something crazy. There is no documented single regimen. Daily steroids in the lowest possible dose, anywhere from 2.5 to 10, is probably the preferred regimen for anywhere from 3 to 7 days with a firm directive to stop. You don't want to start steroids that you can't stop.
And then lastly, it's a little bit like gout. Gout patients who have three or more flares in a year are candidates for urate-lowering therapy. A rheumatoid patient who has three or more flares without good explanation is a candidate for a change in DMARD or biologic or targeted synthetic therapy.
Let's move on and talk about RA patients — especially seropositive patients — who are higher risk. Remember the 3S rule, S being sex, seropositivity, and smoking. Sex being male. If you have those three, you have a
significantly sevenfold higher odds of developing usual interstitial pneumonitis or ILD. ILD when it's found is associated with a significantly higher risk, three-fold higher risk of serious hospitalizable infections. It's also associated with a three to fivefold higher risk of mortality, especially in the next 10 years.
ACR put out guidelines a few years ago. The problem with guidelines and treatment of ILD is it's all expert opinion, no good evidence to support the recommendation. First line therapy from the ACR is either mycophenolate, azathioprine or rituximab. And when that fails, you can consider using maybe cyclophosphamide and maybe short-term steroids.
EULAR last year did better with its guidelines basically saying that all patients with ILD don't really have to be treated, they do have to be monitored, and if they have a reason to treat them you can use drugs that will help in ILD as well as in their RA. This includes abatacept, rituximab, JAK inhibitors, tocilizumab, steroids, azathioprine. If they start to develop more severe or progressive ILD they need a combination of immunosuppressives. If they develop progressive pulmonary fibrosis, EULAR says you can use the anti-fibrotic drugs nintedanib or combinations of nintedanib with immunosuppressives, and then lastly UIP pattern should get pirfenidone.
Let's talk about D2T in the last few minutes. Defined by EULAR as having disease activity that's unacceptable to both patient and doctor, especially in the face of having failed two or three biologic or targeted synthetics of different mechanisms of action. Again, it's two for D2T RA, it's three for poly-refractory RA. People who meet this definition are usually younger, have enthesitis, seropositivity, they're on steroids, they have erosions, they may be smokers, they're often obese, have fibromyalgia and depression.
The important thing here is to recognize some half of the D2T RAs are going to be from RA and inflammation and not having the right immunosuppressive or biologic agent. The other half are going to be from fibromyalgia and functional disease. So the definition here is divided up into NIRA and PIRA. NIRA — non-inflammatory refractory RA — that's usually fibromyalgia-like disease, and PIRA — persistent inflammatory refractory RA. You can make that distinction based on the features: if they have elevated sed rates, if they have swollen joints, if they have CRPs that are elevated, if the DAS28-CRP is high and they have ultrasound evidence of synovitis, they're probably a PIRA, right? And they may need more aggressive anti-RA kind of therapies. However, if they don't have those things and they're obese and they have many tender joints, not some but no swollen joints, and they have criteria for fibromyalgia, poor sleep, and tender points, then they're NIRA, a non-inflammatory, and they need to be treated differently.
If you think about it, the PIRAs are people that have lots of joints, extra-articular manifestations, acute phase reactants, seropositivity, erosions, shared epitope. The NIRAs are people who are non-adherent, bad behaviors, wrong diagnosis, coexistent functional disease, depression, anxiety, etc.
So the question — one more thing about people who are difficult to treat — once you fail your first line therapy or first line combination, subsequent choices are less likely to be successful. That's the bad news. Failure begets more failure. Get it right the first time and be aggressive with your second regimen and get that right. Otherwise, when you're cycling through therapies, you're not going to be doing very well.
You have lots of drugs to choose from. How should you consider this diagnosis? These are either the wrong diagnosis, the wrong patient, the wrong doctor — these are the ways to be thinking about that. For wrong diagnoses, I'm thinking about patients who have seronegatives that may have something else or that you just misdiagnosed RA. It could also be that you're mistaking flares of fibromyalgia NIRA, or flares of depression and poor sleep, with what you think is — or the patient thinks is — RA but is not.
So let's just talk a little bit about hell traits or bad traits, patients that are not going to do well. And this is kind of functional era stuff. The patients who are non-compliant, patients who think that they never do good on anything and they're doomed to fail. They are bad at managing their disease. They're poor sleepers. They have anxiety, depression, and you know, they're magical thinkers. They don't want to take vaccines out of fear. They don't want to take a drug because of the printout from the pharmacy.
Recognize that depression is a major problem in rheumatic disease patients. In RA, it's seen in up to 50% of patients. In RA, there's a bidirectional relationship between having depression and getting more RA or having RA and getting depression. Bad news is the Danish registry shows RA patients with depression have a three-fold higher risk of mortality.
That is not good. Seronegative RA, what is it? It's either seronegative RA, but it could be palindromic rheumatism. It could be polymyalgia. It could be undifferentiated arthritis, inflammatory arthritis. The bottom line is seronegative arthritis — each time you see them is your opportunity to rediagnose them correctly or consider other diagnoses.
In studies of patients with seronegative RA that were followed for many years, as much as two-thirds of them can change their diagnosis to something like PMR, psoriatic arthritis, spondyloarthritis, or even osteoarthritis. It's important to know this happens.
The other unifying feature of people who are misdiagnosed is that they have atypical presentations, longer time to make a diagnosis. They are more likely to fail multiple DMARDs, biologics, and have DMARD toxicities.
RA that's often misdiagnosed is usually either tophaceous gout, psoriatic arthritis, erosive OA, enteropathic arthritis, calcium pyrophosphate deposition disease often caused by hemochromatosis or an endocrinopathy, the early phase of a CTD, PMR, and then it gets really rare after that.
When it comes to treating RA patients that have prior signs of inflammation — acute phase reactions, ultrasound — your next choice has got to be a smart choice and is often dictated by the patient's history, comorbidities, things that they can take and not take. You can get a download from RheumNow.com that will talk about DMARD prescribing in the face of comorbidity.
So if they have diverticulitis, you shouldn't be using prednisone, JAK inhibitors, or IL-6. You can use anything else. If they have TB as a concern, you should not be using any TNF inhibitors or prednisone, but it is safe to use IL-1 inhibitors, rituximab, abatacept, IL-6 inhibitors, IL-17 inhibitors, JAK inhibitors, etc. Again, sometimes comorbidities and toxicities help you to back into what you may do.
And then lastly, I'll give you seven drugs that I've used to manage RA that's not controlled on the things that are usually FDA approved that you probably haven't used. This includes anakinra and gold and cyclophosphamide and cyclosporine. All of those are FDA approved in RA. I have occasionally used and had some success in using mycophenolate, apremilast, or an IL-17 inhibitor, especially if it's a seronegative patient.
Anyway, this is the approach and management of patients with difficult-to-treat RA. Watch for more advanced practice rheumatology.
So first let's talk about flares in RA. They're common. They happen 30 to 60% of patients. And there are many studies that show this happens most frequently when you start to withdraw therapy. I don't know why we do this. I don't do this. You spend a lot of time, effort with trial and error trying to find the right drug and combination of drugs to control a chronic systemic inflammatory disorder that has deadly complications. And then once you achieve a great response, the patient and you want to stop therapy. I don't think that's a really good idea at all.
So these occur frequently. They're going to occur if you taper DMARD or biologic therapy. They're definitely going to occur if you stop DMARD or biologic therapy. And there are significant consequences to these flares. One flare not so bad. You can manage it with temporary medicines, but repeated flares will have worse 12-month outcomes in the things that matter most to the patient. Surprisingly, there will be more X-ray progression with repeated flares and a higher cardiovascular risk. And lastly, there are certainly economic consequences to flares with being out of work, more health care utilization, more comorbidity management.
How do you manage flares? The best way to manage flares is to avoid a flare. Keep them well controlled. Keep them on stable therapy. The goal is to be boring and stable. This is working. Let's not change a thing. Just follow them. Don't taper. Don't stop DMARDs or biologics. The goal is remission or low disease activity state in some.
Secondly, I think you should be documenting the flares. Often patients will call and say, "I'm flaring," and they'll be managed over the phone without ever being seen or without any kind of metric being used to document the flare. You can use remote assessment tools or telemedicine or surveys over the phone to come up with a RAPID3 score, a PAS score. There are other things that you could do, or you could bring them in and do a joint count and a CRP, or whatever it is that you like to follow in your clinic.
The treatments for flares are thankfully simple, cheap, and effective, but they do have toxicities. The problem is they're really not that effective. And often, I think it's time and rest that will be more effective for most flares. But we'll talk about management of D2T RA and how that impacts outcomes.
But for a flare, what are your choices? Analgesics, acetaminophen, tramadol, weak narcotics, non-steroidals. You know, these have been largely shown to not work or have minimal effect, but only impose risk. I do use a fair amount of extended-release acetaminophen. I think most people don't use acetaminophen correctly, meaning they're using short-acting 325–500 milligram acetaminophen and not the long-acting acetaminophen of 650 milligrams. I will up their dose to two to three pills twice a day during flares. With or without a non-steroidal in low dose, with or without a low dose of steroids, but you worry about toxicity, do you not? Especially with non-steroidals, for people who shouldn't be taking non-steroidals.
You always recommend rest, you know, cutting back on activities, cutting back on exercise, stop doing the thing that caused the flare. Those would be smart. And then steroids. Everybody's got a game they play with steroids. You know, come in for a steroid shot or take a Medrol dose pack or, you know, take 10 milligrams a day for 3 days or start out with 15 milligrams a day for 2 days, 10 milligrams a day for 3 days, 5 milligrams a day for four, something crazy. There is no documented single regimen. Daily steroids in the lowest possible dose, anywhere from 2.5 to 10, is probably the preferred regimen for anywhere from 3 to 7 days with a firm directive to stop. You don't want to start steroids that you can't stop.
And then lastly, it's a little bit like gout. Gout patients who have three or more flares in a year are candidates for urate-lowering therapy. A rheumatoid patient who has three or more flares without good explanation is a candidate for a change in DMARD or biologic or targeted synthetic therapy.
Let's move on and talk about RA patients — especially seropositive patients — who are higher risk. Remember the 3S rule, S being sex, seropositivity, and smoking. Sex being male. If you have those three, you have a
significantly sevenfold higher odds of developing usual interstitial pneumonitis or ILD. ILD when it's found is associated with a significantly higher risk, three-fold higher risk of serious hospitalizable infections. It's also associated with a three to fivefold higher risk of mortality, especially in the next 10 years.
ACR put out guidelines a few years ago. The problem with guidelines and treatment of ILD is it's all expert opinion, no good evidence to support the recommendation. First line therapy from the ACR is either mycophenolate, azathioprine or rituximab. And when that fails, you can consider using maybe cyclophosphamide and maybe short-term steroids.
EULAR last year did better with its guidelines basically saying that all patients with ILD don't really have to be treated, they do have to be monitored, and if they have a reason to treat them you can use drugs that will help in ILD as well as in their RA. This includes abatacept, rituximab, JAK inhibitors, tocilizumab, steroids, azathioprine. If they start to develop more severe or progressive ILD they need a combination of immunosuppressives. If they develop progressive pulmonary fibrosis, EULAR says you can use the anti-fibrotic drugs nintedanib or combinations of nintedanib with immunosuppressives, and then lastly UIP pattern should get pirfenidone.
Let's talk about D2T in the last few minutes. Defined by EULAR as having disease activity that's unacceptable to both patient and doctor, especially in the face of having failed two or three biologic or targeted synthetics of different mechanisms of action. Again, it's two for D2T RA, it's three for poly-refractory RA. People who meet this definition are usually younger, have enthesitis, seropositivity, they're on steroids, they have erosions, they may be smokers, they're often obese, have fibromyalgia and depression.
The important thing here is to recognize some half of the D2T RAs are going to be from RA and inflammation and not having the right immunosuppressive or biologic agent. The other half are going to be from fibromyalgia and functional disease. So the definition here is divided up into NIRA and PIRA. NIRA — non-inflammatory refractory RA — that's usually fibromyalgia-like disease, and PIRA — persistent inflammatory refractory RA. You can make that distinction based on the features: if they have elevated sed rates, if they have swollen joints, if they have CRPs that are elevated, if the DAS28-CRP is high and they have ultrasound evidence of synovitis, they're probably a PIRA, right? And they may need more aggressive anti-RA kind of therapies. However, if they don't have those things and they're obese and they have many tender joints, not some but no swollen joints, and they have criteria for fibromyalgia, poor sleep, and tender points, then they're NIRA, a non-inflammatory, and they need to be treated differently.
If you think about it, the PIRAs are people that have lots of joints, extra-articular manifestations, acute phase reactants, seropositivity, erosions, shared epitope. The NIRAs are people who are non-adherent, bad behaviors, wrong diagnosis, coexistent functional disease, depression, anxiety, etc.
So the question — one more thing about people who are difficult to treat — once you fail your first line therapy or first line combination, subsequent choices are less likely to be successful. That's the bad news. Failure begets more failure. Get it right the first time and be aggressive with your second regimen and get that right. Otherwise, when you're cycling through therapies, you're not going to be doing very well.
You have lots of drugs to choose from. How should you consider this diagnosis? These are either the wrong diagnosis, the wrong patient, the wrong doctor — these are the ways to be thinking about that. For wrong diagnoses, I'm thinking about patients who have seronegatives that may have something else or that you just misdiagnosed RA. It could also be that you're mistaking flares of fibromyalgia NIRA, or flares of depression and poor sleep, with what you think is — or the patient thinks is — RA but is not.
So let's just talk a little bit about hell traits or bad traits, patients that are not going to do well. And this is kind of functional era stuff. The patients who are non-compliant, patients who think that they never do good on anything and they're doomed to fail. They are bad at managing their disease. They're poor sleepers. They have anxiety, depression, and you know, they're magical thinkers. They don't want to take vaccines out of fear. They don't want to take a drug because of the printout from the pharmacy.
Recognize that depression is a major problem in rheumatic disease patients. In RA, it's seen in up to 50% of patients. In RA, there's a bidirectional relationship between having depression and getting more RA or having RA and getting depression. Bad news is the Danish registry shows RA patients with depression have a three-fold higher risk of mortality.
That is not good. Seronegative RA, what is it? It's either seronegative RA, but it could be palindromic rheumatism. It could be polymyalgia. It could be undifferentiated arthritis, inflammatory arthritis. The bottom line is seronegative arthritis — each time you see them is your opportunity to rediagnose them correctly or consider other diagnoses.
In studies of patients with seronegative RA that were followed for many years, as much as two-thirds of them can change their diagnosis to something like PMR, psoriatic arthritis, spondyloarthritis, or even osteoarthritis. It's important to know this happens.
The other unifying feature of people who are misdiagnosed is that they have atypical presentations, longer time to make a diagnosis. They are more likely to fail multiple DMARDs, biologics, and have DMARD toxicities.
RA that's often misdiagnosed is usually either tophaceous gout, psoriatic arthritis, erosive OA, enteropathic arthritis, calcium pyrophosphate deposition disease often caused by hemochromatosis or an endocrinopathy, the early phase of a CTD, PMR, and then it gets really rare after that.
When it comes to treating RA patients that have prior signs of inflammation — acute phase reactions, ultrasound — your next choice has got to be a smart choice and is often dictated by the patient's history, comorbidities, things that they can take and not take. You can get a download from RheumNow.com that will talk about DMARD prescribing in the face of comorbidity.
So if they have diverticulitis, you shouldn't be using prednisone, JAK inhibitors, or IL-6. You can use anything else. If they have TB as a concern, you should not be using any TNF inhibitors or prednisone, but it is safe to use IL-1 inhibitors, rituximab, abatacept, IL-6 inhibitors, IL-17 inhibitors, JAK inhibitors, etc. Again, sometimes comorbidities and toxicities help you to back into what you may do.
And then lastly, I'll give you seven drugs that I've used to manage RA that's not controlled on the things that are usually FDA approved that you probably haven't used. This includes anakinra and gold and cyclophosphamide and cyclosporine. All of those are FDA approved in RA. I have occasionally used and had some success in using mycophenolate, apremilast, or an IL-17 inhibitor, especially if it's a seronegative patient.
Anyway, this is the approach and management of patients with difficult-to-treat RA. Watch for more advanced practice rheumatology.
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