RheumNow Podcast Rituximab Monitoring (5.31.19) Save
RheumNow Podcast Rituximab Monitoring (5.31.19) by Dr. Cush
Transcription
It's the 05/31/2019. This is a RheumNow podcast. I'm doctor Jack Cush, executive editor of roomnow.com. You are two weeks away. Get your tickets now.
RheumNow will be there covering the meeting for you. So hope you'll enjoy that. Look for our expanded coverage. Today, we're gonna talk about disappointing drugs from the fibromyalgia world, the cost of physician burnout, and which is the safer drug, allopurinol or febuxostat? Or does it even matter when we're talking about gout?
That's our first study. It comes from a Korean national Health Insurance database which looked at prescriptions febuxostat and first time initiators of allopurinol in patients with gout. Almost forty thousand patients were studied over a several year period and they were looking at the risk of major cardiac events like MI, TIA, stroke, a few other cardiac events, basically MACE, major adverse cardiac events. The incidence with allopurinol was one point eight nine. The incidence with febuxostat one point eight four per one 100 patient years.
Not significantly different, the hazard ratios were the same, suggesting that at least in this Asian population, the drugs were not only equally potent, but equally safe. Now that's a big issue of discussion recently because as you know, in January 2019, the FDA had a hearing on the safety of febuxostat and came away with some changes in the package labeling suggesting that febuxostat may have several, an edge in more cardiac, risk than does allopurinol. So much so that they said number one, any patients going on urate lowering therapy should start on allopurinol first and then consider fabuxtat if needed or if there's an allergy to allopurinol then fabuxtat could be considered. But that patient should know that there's a possibly a higher risk with fabuxtat than with allopurinol. Turns out, again, if you look at a lot of these studies, it sometimes looks like it's a little more with febuxostat, sometimes it's about the same with allopurinol, sometimes allopurinol is even a little bit worse.
You know, pound for pound all studies, you know, there is a slight edge and more events with febuxostat. Again, I think these drugs work, I think all drugs work when you use them in gout and when you set expectations with patients on how they're to be monitored. But gout patients are at high risk for these cardiac events. One because they have so much comorbidity. Two because often they're not well controlled as far as this inflammatory disease.
Another gout report comes on, comes from China, very interesting study of one hundred and thirty patients with tophaceous gout and about thirty three of them develop ulcerations of their tophi. And this report was on what are the risk factors for developing an ulcerated tophis in someone with gout. After their analysis turns out the factors that stood out were glucocorticoid overuse, how long you had the tophi, and the number of tophi. So it's not necessarily the size or it's really the duration of the tophis and how many tophi were the factors that were most predictive of tophaceous ation. So a few interesting studies from, fibromyalgia and fibromyalgia drugs.
The first is in, juvenile fibromyalgia where they studied, duloxetine versus placebo in one hundred and eighty four patients with juvenile fibromyalgia for thirteen weeks. They escalated the dose from thirty to sixty milligrams a day and guess what? Duloxetine did not meet its primary endpoint, which was the mean change in something called the brief pain inventory, the BPI, a pain measure that was used in fibromyalgia. When they looked at that as a discrete measure at any one time, looked like Cymbalta was better with either 30% or 50% reductions in BPI compared to placebo, but at their primary endpoint it failed. And that's what the drug is supposed to do.
As you know, this is an approved therapy, at least in adults, but not yet in children. Lyrica was also recently studied not in fibromyalgia, but in, treating generalized tonic clonic seizures. As you know, Lyrica is, Pregabalin is approved by the FDA for use in fibromyalgia neuropathy as adjunctive therapy in partial onset seizures. But in this particular study, a phase three trial that was studied and found to not actually meet its primary endpoint in reducing frequency of primary generalized tonic clonic seizures. It's kind of disappointing because as you know, Lyrica is a descendant of gabapentin, also an anti seizure drug, and it, you know, it should have worked here, but it didn't.
All this to say duloxetine, Lyrica, I use them. I don't have a lot of success with them. To me, it's more of a marker of a patient who's going to be hard to treat, who's not likely to respond to much. They're going to be a handful and they have difficult disease. I wish these agents were more potent.
I wish we had better agents or better approaches to fibromyalgia. I don't think we do. There should be a big call for more research in this area. Another drug, another disease that merits a lot of research is certainly scleroderma. Japanese study of almost 200 patients correlated, skin thickness scores, the modified Rodnan skin score organ disease and found with higher skin thickness scores, had a significantly higher risk of interstitial lung disease, restrictive lung disease, and lower DLCOs or diffusion impairment that was significant.
I posted this one because I think it's well known that advancing skin disease is associated with a greater risk of organ damage, not just lung, but also kidney and maybe heart. But in this study, they actually based a lot of their findings on the modified Rodden Skin score. In a disease that doesn't have a lot going forward, at least it has this one very good measure, and that really has great predictive value and is a primary endpoint in almost all the studies. If you have a scleroderma patient, whether it's limited systemic sclerosis or diffuse systemic sclerosis, and they're not getting these done serially, you're making a big mistake. You do joint counts in RA, you follow CPK in myositis.
This is the only thing you can hang your hat on in patients with systemic sclerosis, or it's one of the main things and it's very reproducible. You are your own control. The skin is scored in I think 17 or 18 different areas. It's the face, chest, abdomen, and then bilaterally, the upper arm, the forearm, the back of the hand, and the fingers. And then the lower extremities, it's the thigh, lower leg, and foot.
That's bilaterally. The total score is 51 when you rate patients on a scale of zero to three, zero normal skin mobility, mild thickness, moderate thickness and severe thickness, severe thickness, you can't pinch up any skin on the back of the finger or the hand and whatnot. It's worth doing, it's worth recording and following serially in all your patients. So an interesting study looked at leflinamide in patients with psoriatic disease. Actually a meta analysis of multiple studies looked at whether this is a useful therapy in either the skin disease or the joint disease.
Turns out that it's really good at the joint disease as you probably would guess. They only looked at the mean SRC, outcome measures, not ACR twenty, where there was seventy seven percent success rate. The skin disease success rate not so good only using Posse fifty outcomes not the usual only forty eight percent respond, Posse seventy five only twenty five percent respond in this day and age are a lot better drugs to treat the skin. All this to say I've actually used leflunomide quite a bit in both psoriatic arthritis and even as adjunctive therapy in combination with other drugs to treat, aggressive skin disease with fairly good success, fairly good tolerance as far as how it goes. In all these studies, only about a fifteen percent dropout rate.
Think of leflunomide, although it's not an FDA approved drug, it is a targeted therapy that probably merits consideration in psoriatic disease. A study from The UK looked at the, associations of central adiposity or basically your waist circumference in increasing the risk of disease. It was shown that increases the risk of psoriasis and of rheumatoid arthritis but not psoriatic arthritis, which is sort of surprising because obesity has been associated with the risk of both RA and PSA and psoriasis. And this particular study did not show and it's a large UK study. So, again, obesity is a major risk factor for these diseases.
The osteoarthritis initiative has been out there for a long time has been studying osteoarthritis. In this particular study, 4796, almost five thousand patients were treated for, their osteoarthritis. They looked at the adjunctive use of metformin in obese patients with osteoarthritis and showed that actually the use of metformin was associated with significantly reduced rate of medial cartilage loss in the knee, and that's 0.701 versus one point five percent. Basically a fifty percent, almost a fifty percent reduction and a trend in fewer knee replacement surgeries, over a six year period. Now this will only apply to obese patients with a BMI over thirty.
So presumably they're getting their their metformin for diabetes or, or the like but here it shows that it has some protect defense effects. Again, metformin shows up in a lot of different studies as being adjunctive therapy helpful a lot of autoimmune diseases. It may work through a lot of different mediators. In other disease we think it's IL-seventeen mediated. Here it could be nitric oxide, it could be MMPs, it could be cytokines, it could be activation of intracellular mediators that are cell signaling mediators.
Again, it's an interesting adjunctive therapy in many of our patients. So, an interesting study looked at the, retention of biologic therapy in patients with ankylosing spondylitis. And following a local, this is the German cohort, followed a large number of patients, who were starting a new TNF, their first TNF inhibitor and showed at one year seventy four percent were still on that TNF inhibitor. However, after five years only, half the patients, forty six percent were on a TNF inhibitor at that time. A number of them had switched to another, biologic and usually another TNF inhibitor such that at five years sixty three percent were on some biologic, forty six percent were only on the first biologic.
Over time, one third of patients go off of therapy. Over time are the ones who stay on therapy, of the two thirds, half of them stay on the same drug and the others go on to a different drug and the ones who stay on the same drug, actually the ones who stay on the same drug, half of them take a reduced dose and half of them take the same dose. So the idea is that the majority of patients with spondylitis will stay on a biologic therapy, but there is a significant one third of patients who will go off of therapy. Who are these people? How they get on the therapy?
Were they reasonable starts to begin with? I find that interesting data. The analyst of internal medicine reported this week on the cost of physician burnout. This was, a simulated modeling study, and they specifically looked at what would be the cost to society, to The United States. If you look at things like physicians who are going to retire or reduce their hours of work.
It was estimated that the cost to The US per annum is $4,600,000,000 The cost to an organization like a hospital who employs a physician who may want to, you know, bow out or reduce their hours is about $7,600 physician per year due to burnout. This is a substantial, financial hit to the healthcare system. Forget about what it does to the individuals, physicians who are becoming, you know, afflicted by this. I think this merits a serious nationwide consideration for how we can combat the problem of physician burnout. We know the EMRs are contributing to it.
We know that the workflow has become a little bit ridiculous when you're doing prior authorizations for prednisone and methotrexate. Hello. There's a lot of reasons why, physicians are burning out and I think that this needs to be taken seriously by those who are planning healthcare for the future. Our last report, has to do with the risk of serious infection with rituximab, as you know very commonly used, biologic. It has a risk of serious infection just like all the other biologics which generally about two to five, per 100 patient years.
That's a serious infectious event. The risk in the package insert of rituximab is four point three per one hundred patient years. In this particular study, a single center study, seven hundred patients were treated with rituximab and had their immunoglobulin levels followed. It's kind of interesting because I don't usually do that. In their seven hundred patients about seventy two percent were taking rituximab for their rheumatoid arthritis.
The other twenty five percent were taking for other rheumatic diseases, mostly lupus, some myositis and then some others. The overall rate of SIEs in this cohort, single center cohort was nine point eight per 100 patient years. That's about double the rate in the literature. So this is the real world where real things happen at a much higher rate. What they did show was that the risk factors for getting infections, as you might expect, would be having had a prior serious infectious event like a pneumonia or septic arthritis, but also cancer comorbidities, especially chronic lung disease.
Obviously higher corticosteroid doses would increase the risk, but the rituximab related, risk factors are interesting. It's not B cell numbers. B cell depletion had no predictive value here in developing future serious infectious events. What did have value and has been shown by others including Ronald Van Vollenhaven is the IgG levels. Low IgG levels prior to starting rituximab or after restarting rituximab increases the risk of an SIE.
And we're talking about the rates going up to sixteen point four per one hundred patient years if it's before rituximab or, twenty one point three if it's after rituximab. Another important thing to follow are neutrophil counts. Rituximab associated neutropenia was a risk factor. And lastly, the more you're on rituximab, the longer time of rituximab treatment, the greater the risk of developing a serious infection. So this says don't follow B cell numbers, you should follow IgG prior to and during infusions of rituximab and follow neutrophil counts that you do not want to become neutropenic.
That would obviously be associated with a higher risk of infection, not surprisingly. But there is this phenomenon of, rituximab associated neutropenia. I a slide on that I want to say it's somewhere around six to nine percent of patients will develop that but it's a low number but it does happen. They don't respond to GM CSF, know, growth factor, therapy, you basically have to support them and watch them for infection over time and they can receive subsequent infusions. That's it for this week at RheumNow.
Go to the website, check out these citations to read more on these interesting reports. We'll talk to you next week. Follow us at room at, at EULAR coming up in two weeks.
RheumNow will be there covering the meeting for you. So hope you'll enjoy that. Look for our expanded coverage. Today, we're gonna talk about disappointing drugs from the fibromyalgia world, the cost of physician burnout, and which is the safer drug, allopurinol or febuxostat? Or does it even matter when we're talking about gout?
That's our first study. It comes from a Korean national Health Insurance database which looked at prescriptions febuxostat and first time initiators of allopurinol in patients with gout. Almost forty thousand patients were studied over a several year period and they were looking at the risk of major cardiac events like MI, TIA, stroke, a few other cardiac events, basically MACE, major adverse cardiac events. The incidence with allopurinol was one point eight nine. The incidence with febuxostat one point eight four per one 100 patient years.
Not significantly different, the hazard ratios were the same, suggesting that at least in this Asian population, the drugs were not only equally potent, but equally safe. Now that's a big issue of discussion recently because as you know, in January 2019, the FDA had a hearing on the safety of febuxostat and came away with some changes in the package labeling suggesting that febuxostat may have several, an edge in more cardiac, risk than does allopurinol. So much so that they said number one, any patients going on urate lowering therapy should start on allopurinol first and then consider fabuxtat if needed or if there's an allergy to allopurinol then fabuxtat could be considered. But that patient should know that there's a possibly a higher risk with fabuxtat than with allopurinol. Turns out, again, if you look at a lot of these studies, it sometimes looks like it's a little more with febuxostat, sometimes it's about the same with allopurinol, sometimes allopurinol is even a little bit worse.
You know, pound for pound all studies, you know, there is a slight edge and more events with febuxostat. Again, I think these drugs work, I think all drugs work when you use them in gout and when you set expectations with patients on how they're to be monitored. But gout patients are at high risk for these cardiac events. One because they have so much comorbidity. Two because often they're not well controlled as far as this inflammatory disease.
Another gout report comes on, comes from China, very interesting study of one hundred and thirty patients with tophaceous gout and about thirty three of them develop ulcerations of their tophi. And this report was on what are the risk factors for developing an ulcerated tophis in someone with gout. After their analysis turns out the factors that stood out were glucocorticoid overuse, how long you had the tophi, and the number of tophi. So it's not necessarily the size or it's really the duration of the tophis and how many tophi were the factors that were most predictive of tophaceous ation. So a few interesting studies from, fibromyalgia and fibromyalgia drugs.
The first is in, juvenile fibromyalgia where they studied, duloxetine versus placebo in one hundred and eighty four patients with juvenile fibromyalgia for thirteen weeks. They escalated the dose from thirty to sixty milligrams a day and guess what? Duloxetine did not meet its primary endpoint, which was the mean change in something called the brief pain inventory, the BPI, a pain measure that was used in fibromyalgia. When they looked at that as a discrete measure at any one time, looked like Cymbalta was better with either 30% or 50% reductions in BPI compared to placebo, but at their primary endpoint it failed. And that's what the drug is supposed to do.
As you know, this is an approved therapy, at least in adults, but not yet in children. Lyrica was also recently studied not in fibromyalgia, but in, treating generalized tonic clonic seizures. As you know, Lyrica is, Pregabalin is approved by the FDA for use in fibromyalgia neuropathy as adjunctive therapy in partial onset seizures. But in this particular study, a phase three trial that was studied and found to not actually meet its primary endpoint in reducing frequency of primary generalized tonic clonic seizures. It's kind of disappointing because as you know, Lyrica is a descendant of gabapentin, also an anti seizure drug, and it, you know, it should have worked here, but it didn't.
All this to say duloxetine, Lyrica, I use them. I don't have a lot of success with them. To me, it's more of a marker of a patient who's going to be hard to treat, who's not likely to respond to much. They're going to be a handful and they have difficult disease. I wish these agents were more potent.
I wish we had better agents or better approaches to fibromyalgia. I don't think we do. There should be a big call for more research in this area. Another drug, another disease that merits a lot of research is certainly scleroderma. Japanese study of almost 200 patients correlated, skin thickness scores, the modified Rodnan skin score organ disease and found with higher skin thickness scores, had a significantly higher risk of interstitial lung disease, restrictive lung disease, and lower DLCOs or diffusion impairment that was significant.
I posted this one because I think it's well known that advancing skin disease is associated with a greater risk of organ damage, not just lung, but also kidney and maybe heart. But in this study, they actually based a lot of their findings on the modified Rodden Skin score. In a disease that doesn't have a lot going forward, at least it has this one very good measure, and that really has great predictive value and is a primary endpoint in almost all the studies. If you have a scleroderma patient, whether it's limited systemic sclerosis or diffuse systemic sclerosis, and they're not getting these done serially, you're making a big mistake. You do joint counts in RA, you follow CPK in myositis.
This is the only thing you can hang your hat on in patients with systemic sclerosis, or it's one of the main things and it's very reproducible. You are your own control. The skin is scored in I think 17 or 18 different areas. It's the face, chest, abdomen, and then bilaterally, the upper arm, the forearm, the back of the hand, and the fingers. And then the lower extremities, it's the thigh, lower leg, and foot.
That's bilaterally. The total score is 51 when you rate patients on a scale of zero to three, zero normal skin mobility, mild thickness, moderate thickness and severe thickness, severe thickness, you can't pinch up any skin on the back of the finger or the hand and whatnot. It's worth doing, it's worth recording and following serially in all your patients. So an interesting study looked at leflinamide in patients with psoriatic disease. Actually a meta analysis of multiple studies looked at whether this is a useful therapy in either the skin disease or the joint disease.
Turns out that it's really good at the joint disease as you probably would guess. They only looked at the mean SRC, outcome measures, not ACR twenty, where there was seventy seven percent success rate. The skin disease success rate not so good only using Posse fifty outcomes not the usual only forty eight percent respond, Posse seventy five only twenty five percent respond in this day and age are a lot better drugs to treat the skin. All this to say I've actually used leflunomide quite a bit in both psoriatic arthritis and even as adjunctive therapy in combination with other drugs to treat, aggressive skin disease with fairly good success, fairly good tolerance as far as how it goes. In all these studies, only about a fifteen percent dropout rate.
Think of leflunomide, although it's not an FDA approved drug, it is a targeted therapy that probably merits consideration in psoriatic disease. A study from The UK looked at the, associations of central adiposity or basically your waist circumference in increasing the risk of disease. It was shown that increases the risk of psoriasis and of rheumatoid arthritis but not psoriatic arthritis, which is sort of surprising because obesity has been associated with the risk of both RA and PSA and psoriasis. And this particular study did not show and it's a large UK study. So, again, obesity is a major risk factor for these diseases.
The osteoarthritis initiative has been out there for a long time has been studying osteoarthritis. In this particular study, 4796, almost five thousand patients were treated for, their osteoarthritis. They looked at the adjunctive use of metformin in obese patients with osteoarthritis and showed that actually the use of metformin was associated with significantly reduced rate of medial cartilage loss in the knee, and that's 0.701 versus one point five percent. Basically a fifty percent, almost a fifty percent reduction and a trend in fewer knee replacement surgeries, over a six year period. Now this will only apply to obese patients with a BMI over thirty.
So presumably they're getting their their metformin for diabetes or, or the like but here it shows that it has some protect defense effects. Again, metformin shows up in a lot of different studies as being adjunctive therapy helpful a lot of autoimmune diseases. It may work through a lot of different mediators. In other disease we think it's IL-seventeen mediated. Here it could be nitric oxide, it could be MMPs, it could be cytokines, it could be activation of intracellular mediators that are cell signaling mediators.
Again, it's an interesting adjunctive therapy in many of our patients. So, an interesting study looked at the, retention of biologic therapy in patients with ankylosing spondylitis. And following a local, this is the German cohort, followed a large number of patients, who were starting a new TNF, their first TNF inhibitor and showed at one year seventy four percent were still on that TNF inhibitor. However, after five years only, half the patients, forty six percent were on a TNF inhibitor at that time. A number of them had switched to another, biologic and usually another TNF inhibitor such that at five years sixty three percent were on some biologic, forty six percent were only on the first biologic.
Over time, one third of patients go off of therapy. Over time are the ones who stay on therapy, of the two thirds, half of them stay on the same drug and the others go on to a different drug and the ones who stay on the same drug, actually the ones who stay on the same drug, half of them take a reduced dose and half of them take the same dose. So the idea is that the majority of patients with spondylitis will stay on a biologic therapy, but there is a significant one third of patients who will go off of therapy. Who are these people? How they get on the therapy?
Were they reasonable starts to begin with? I find that interesting data. The analyst of internal medicine reported this week on the cost of physician burnout. This was, a simulated modeling study, and they specifically looked at what would be the cost to society, to The United States. If you look at things like physicians who are going to retire or reduce their hours of work.
It was estimated that the cost to The US per annum is $4,600,000,000 The cost to an organization like a hospital who employs a physician who may want to, you know, bow out or reduce their hours is about $7,600 physician per year due to burnout. This is a substantial, financial hit to the healthcare system. Forget about what it does to the individuals, physicians who are becoming, you know, afflicted by this. I think this merits a serious nationwide consideration for how we can combat the problem of physician burnout. We know the EMRs are contributing to it.
We know that the workflow has become a little bit ridiculous when you're doing prior authorizations for prednisone and methotrexate. Hello. There's a lot of reasons why, physicians are burning out and I think that this needs to be taken seriously by those who are planning healthcare for the future. Our last report, has to do with the risk of serious infection with rituximab, as you know very commonly used, biologic. It has a risk of serious infection just like all the other biologics which generally about two to five, per 100 patient years.
That's a serious infectious event. The risk in the package insert of rituximab is four point three per one hundred patient years. In this particular study, a single center study, seven hundred patients were treated with rituximab and had their immunoglobulin levels followed. It's kind of interesting because I don't usually do that. In their seven hundred patients about seventy two percent were taking rituximab for their rheumatoid arthritis.
The other twenty five percent were taking for other rheumatic diseases, mostly lupus, some myositis and then some others. The overall rate of SIEs in this cohort, single center cohort was nine point eight per 100 patient years. That's about double the rate in the literature. So this is the real world where real things happen at a much higher rate. What they did show was that the risk factors for getting infections, as you might expect, would be having had a prior serious infectious event like a pneumonia or septic arthritis, but also cancer comorbidities, especially chronic lung disease.
Obviously higher corticosteroid doses would increase the risk, but the rituximab related, risk factors are interesting. It's not B cell numbers. B cell depletion had no predictive value here in developing future serious infectious events. What did have value and has been shown by others including Ronald Van Vollenhaven is the IgG levels. Low IgG levels prior to starting rituximab or after restarting rituximab increases the risk of an SIE.
And we're talking about the rates going up to sixteen point four per one hundred patient years if it's before rituximab or, twenty one point three if it's after rituximab. Another important thing to follow are neutrophil counts. Rituximab associated neutropenia was a risk factor. And lastly, the more you're on rituximab, the longer time of rituximab treatment, the greater the risk of developing a serious infection. So this says don't follow B cell numbers, you should follow IgG prior to and during infusions of rituximab and follow neutrophil counts that you do not want to become neutropenic.
That would obviously be associated with a higher risk of infection, not surprisingly. But there is this phenomenon of, rituximab associated neutropenia. I a slide on that I want to say it's somewhere around six to nine percent of patients will develop that but it's a low number but it does happen. They don't respond to GM CSF, know, growth factor, therapy, you basically have to support them and watch them for infection over time and they can receive subsequent infusions. That's it for this week at RheumNow.
Go to the website, check out these citations to read more on these interesting reports. We'll talk to you next week. Follow us at room at, at EULAR coming up in two weeks.
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