RheumNow Podcast - Methotrexate Mechanisms (2.28.20) Save
RheumNow Podcast - Methotrexate Mechanisms (2.28.20) by Dr. Cush
Transcription
It's the 02/28/2020. This is the RheumNow podcast, and I'm doctor Jack Cush, executive editor of roomnow.com. This podcast is brought to you by roomnow.live. Check it out. Pot smoking geriatricians, what?
Bariatric surgery to treat rheumatoid arthritis, even crazier. And can you name what nonsteroidals are available in IV form? You'll know the answer to all these today. We're going to start with a report about the safety of Cirilumab, the last and newest of the IL-six inhibitors to be approved for use in rheumatoid arthritis. Cirulumab has been out for a few years now, we see reports of it and its efficacy that seems to match that of its predecessor and all that's comforting.
I think there has been growing use of it, I think that it's partly because it's a new drug, maybe it's not growing fast enough, my own opinion, but realize that there's a lot of safety data that's been accrued on this and a recent publication in rheumatology, I think it was headed by Roy Fleishman, all the investigators associated with these studies, sort of accentuates the safety profile of this drug. Almost 3,000 patients received cerulimab plus a DMARD, almost, five hundred patients who are on monotherapy, followed for up to seven years, or a total of over 8,000 patient years of exposure, and the adverse event rates are reported per 100 patient years. Serious adverse events, six to nine, that's about on par what you'd expect. Serious infectious events, 3.7 is about what you'd expect for, a biologic and certainly, looks very good to other biologics and the IL-six inhibitors. Zoster is a very low frequency event, we know Zoster is seems to be more frequent in people who are on JAK inhibitors, but the event rate is here as it looks like it's about five to six per 1,000 patient years.
GI perforations very low, it's point one or no, GI perforations, intestinal perforations per 100 patient years, cancer risk also very low, point six, point seven per 100 patient years. The frequency of ANC levels less than 1,000, I thought was surprising but that's what's been reported and it's about thirteen to fifteen percent reminding you that you do need to follow WBC counts, lipid counts, and also LFTs, but ANC. And again, that's probably not, a dangerous number. I think it's the lymphopenia that would make it dangerous, less than five hundred, but I would urge you to follow ANC levels in people who are taking all biologics, but even the IL-six inhibitors and the JAK inhibitors as well. A very interesting report comes to us this week from the Lancet Endocrinology, which I know you all read.
Metformin being used as a means of controlling steroid toxicity. This is a study of non diabetic individuals who had an inflammatory disorder which required the use of steroids, prednisone greater than twenty milligrams a day, and they were either given, placebo or metformin. Those on metformin had less pneumonia, less serious infections, and then less markers of carbohydrate, lipid, and liver and bone metabolic metabolic abnormalities compared to those who were on placebo. Being on metformin didn't prevent the weight gain and truncal fat associated with steroid use, but it did prevent and improve, infectious risk and a number of these other biomarkers, of what goes wrong when someone is on steroids. It's quite encouraging.
You know, metformin is sort of a sneaky, potentially very advantageous drug to be on because it has immunologic effects on IL-seventeen, Th-seventeen cells, it seems to be adjunctive in the control of autoimmune and inflammatory disease. We need more research about the use of, metformin like this research done here in patients on steroids. A recent report looks at the, benefits of potentially doing faster hip replacement surgery. This is called the hip attack study, and it looked at whether patients had, who had a hip fracture were to receive immediate, like surgery within a few hours versus standard of care, which usually is within a day or two. In this study of almost 3,000 individuals, the average time to accelerated hip surgery was six hours, standard hip surgery was twenty four hours, and there was no differences with regard to the outcome in these individuals.
I did however find it a little alarming that the risk of death is nine to ten percent in both groups and infection was obviously a lot less. So, I think that this tells you that patients who have hip replacements and of course they're elderly, I mean hip surgery, hip fracture and the need for surgery, they tend to be elderly, they tend to have comorbidities, the death rate may not be that surprising, but to me it was surprising. I think again, we need to be expeditious in getting our patients with this problem to the surgeon, and they can do their surgery within a day or so. Cannabis in the elderly, are you kidding me? I was sort of surprised at this, but I think this was a CDC statistic that showed in two thousand and six the number of elderly people 65 who use cannabis in The United States was about four in a thousand or point four percent.
In 2016 this had risen up to two point nine percent or that's thirty in a thousand or three per hundred. Clearly this must be related to the opioid crisis, the lack of availability of stronger narcotics and patients looking for either illicit alternatives, and this may be being the safest of the illicit alternatives. Of course, it also follows the widespread introduction of cannabis in multiple states. So, this is being used by the elderly and the question is, what's the downside, what's the safety, what's the efficacy? Being aware of it may be your first step.
The safety of biologics was studied by the Brazilian Biologics Registry in, eleven hundred RA patients and almost six hundred SPA patients, and found that serious, infectious events were common and increased in those that took the TNF inhibitors within, a threefold increased risk of an SIE if you were on a TNF inhibitor. That's an adjusted IR of 2.96. Now, it stands to reason it would be elevated, people who are sicker and people who are more inflamed and need stronger biologics do have a higher risk of infection, and so again it's something we need to realize it's part and parcel of who we're treating here. But if you use a second TNF inhibitor in that same population, the risk of infection is still, serious infection is still elevated at one point five five with the second go around of a TNF inhibitor. Being ever vigilant is the way to safeguard against serious infections in patients on biologics.
Homocysteine and lupus was analyzed via, I guess, a meta analysis of many studies. Turns out there were 36 studies that have looked at this that compared almost three thousand lupus patients who were tested to 3,000 controls who were tested, and turns out that homocysteine levels were significantly elevated in lupus patients compared to healthy controls, and that elevation was predicted by age, disease duration, disease activity, and having a BMI of greater than twenty three. This is a Chinese study, so a BMI of greater than twenty three was obese and higher. And this clearly says that, you know, the collagen vascular disease, vascular disease that is lupus could be identified further or contributed to further by hyper homocystinemia and that may be something we should be looking for and treating in the future. The FDA this past week approved a new IV form of a non steroidal, in this case it was meloxicam, It's called Angeso, a n g j e s o.
It's for the treatment of moderate to severe pain in adults with arthritis. It's for short term use. It's based on three of phase two, I'm sorry, two phase three trials, and one phase three safety study. This joins a number of nonsteroidals that are on the market. I did a little bit of research on there and as you know, Ketrololac is an IV nonsteroidal, but there are IV forms of Indomethacin, Ibuprofen, there was an IV form of I think Vioxx back in the day, there's also an IV form of Diclofenac and now there's an IV form of Meloxicam.
A cross sectional study looked at the association of periodontal disease with rheumatoid arthritis. Again, has been shown before, but nonetheless interesting to note that periodontal disease is associated with both the presence of CCP, antibodies and that the severity of periodontal disease also has association with disease activity. This was a study of one hundred and thirty nine RA patients. There's a nice free open label, reopen read on the mechanism of action of methotrexate from the methotrexate guy himself, doctor Bruce Cronstein from NYU, where he goes over the many potential mechanisms underlying the effects of methotrexate, including adenosine release, nitric oxide, synthase, uncoupling, effects on NF kappa b, and an increase was called link RNA p 21, and that's a a non coding intergenic RNA p 21. You know, you can learn more about this by going to RheumNow Live.
Bruce is one of our featured speakers on how methotrexate works at RheumNow Live that you can register for now. And two more reports, bariatric surgery improves rheumatoid arthritis, know, have been other reports talking about weight loss and bariatric surgery specifically suggesting that may be associated with disease control. We do know that bariatric surgery and weight loss doesn't seem to reduce risk, although there are studies that say that being obese increases the risk of developing RA. This particular study mirrors a few others that could have gone before it. This was sixty five patients, with a BMI of about thirty eight, half of whom went on to receive bariatric surgery with drug therapy, other just drug therapy.
Those had the bariatric surgery plus pharmacotherapy had better disease control, their ACR 20 responses were seventy five versus fifty two in the non bariatric surgery group, their ACR 50 was thirty one versus twenty one percent. Other markers of activity including C Dye were improved. Again, weight loss is important and bariatric surgery could be the means by which you get control of patients who are difficult to control but yet obese. There's a nice report from the Swedish SCAPIS population study, this stands for the Swedish Cardiopulmonary BioImage study, and this study they found that hyperuricemia predisposed to coronary artery disease as measured by a calcium artery, score, a calcium, score that was, twice elevated in in in let's see actually the calc score and diabetes was twice as common, in in RA patients. Let me get this right.
Let me see here. Hyperuricemia was associated with diabetes and a calcium artery score, not rheumatoid arthritis. The diabetes and elevated scores, we do know that hyperuricemia is a toxin basically for the vasculature. Hyperuricemia and gout are associated with increased risk of cardiovascular events, cardiovascular disease. This just says that population elevations of hyperuricemia can give subclinical increases in those calcium artery scores which may predict future events in some people.
Twice as common in men than women. Women, it wasn't so significant. Men, it was highly significant. That's it for this week. Go to the website.
Read more about these interesting reports. Go to roomnow.live and register for our meeting coming up in two weeks. Next time.
Bariatric surgery to treat rheumatoid arthritis, even crazier. And can you name what nonsteroidals are available in IV form? You'll know the answer to all these today. We're going to start with a report about the safety of Cirilumab, the last and newest of the IL-six inhibitors to be approved for use in rheumatoid arthritis. Cirulumab has been out for a few years now, we see reports of it and its efficacy that seems to match that of its predecessor and all that's comforting.
I think there has been growing use of it, I think that it's partly because it's a new drug, maybe it's not growing fast enough, my own opinion, but realize that there's a lot of safety data that's been accrued on this and a recent publication in rheumatology, I think it was headed by Roy Fleishman, all the investigators associated with these studies, sort of accentuates the safety profile of this drug. Almost 3,000 patients received cerulimab plus a DMARD, almost, five hundred patients who are on monotherapy, followed for up to seven years, or a total of over 8,000 patient years of exposure, and the adverse event rates are reported per 100 patient years. Serious adverse events, six to nine, that's about on par what you'd expect. Serious infectious events, 3.7 is about what you'd expect for, a biologic and certainly, looks very good to other biologics and the IL-six inhibitors. Zoster is a very low frequency event, we know Zoster is seems to be more frequent in people who are on JAK inhibitors, but the event rate is here as it looks like it's about five to six per 1,000 patient years.
GI perforations very low, it's point one or no, GI perforations, intestinal perforations per 100 patient years, cancer risk also very low, point six, point seven per 100 patient years. The frequency of ANC levels less than 1,000, I thought was surprising but that's what's been reported and it's about thirteen to fifteen percent reminding you that you do need to follow WBC counts, lipid counts, and also LFTs, but ANC. And again, that's probably not, a dangerous number. I think it's the lymphopenia that would make it dangerous, less than five hundred, but I would urge you to follow ANC levels in people who are taking all biologics, but even the IL-six inhibitors and the JAK inhibitors as well. A very interesting report comes to us this week from the Lancet Endocrinology, which I know you all read.
Metformin being used as a means of controlling steroid toxicity. This is a study of non diabetic individuals who had an inflammatory disorder which required the use of steroids, prednisone greater than twenty milligrams a day, and they were either given, placebo or metformin. Those on metformin had less pneumonia, less serious infections, and then less markers of carbohydrate, lipid, and liver and bone metabolic metabolic abnormalities compared to those who were on placebo. Being on metformin didn't prevent the weight gain and truncal fat associated with steroid use, but it did prevent and improve, infectious risk and a number of these other biomarkers, of what goes wrong when someone is on steroids. It's quite encouraging.
You know, metformin is sort of a sneaky, potentially very advantageous drug to be on because it has immunologic effects on IL-seventeen, Th-seventeen cells, it seems to be adjunctive in the control of autoimmune and inflammatory disease. We need more research about the use of, metformin like this research done here in patients on steroids. A recent report looks at the, benefits of potentially doing faster hip replacement surgery. This is called the hip attack study, and it looked at whether patients had, who had a hip fracture were to receive immediate, like surgery within a few hours versus standard of care, which usually is within a day or two. In this study of almost 3,000 individuals, the average time to accelerated hip surgery was six hours, standard hip surgery was twenty four hours, and there was no differences with regard to the outcome in these individuals.
I did however find it a little alarming that the risk of death is nine to ten percent in both groups and infection was obviously a lot less. So, I think that this tells you that patients who have hip replacements and of course they're elderly, I mean hip surgery, hip fracture and the need for surgery, they tend to be elderly, they tend to have comorbidities, the death rate may not be that surprising, but to me it was surprising. I think again, we need to be expeditious in getting our patients with this problem to the surgeon, and they can do their surgery within a day or so. Cannabis in the elderly, are you kidding me? I was sort of surprised at this, but I think this was a CDC statistic that showed in two thousand and six the number of elderly people 65 who use cannabis in The United States was about four in a thousand or point four percent.
In 2016 this had risen up to two point nine percent or that's thirty in a thousand or three per hundred. Clearly this must be related to the opioid crisis, the lack of availability of stronger narcotics and patients looking for either illicit alternatives, and this may be being the safest of the illicit alternatives. Of course, it also follows the widespread introduction of cannabis in multiple states. So, this is being used by the elderly and the question is, what's the downside, what's the safety, what's the efficacy? Being aware of it may be your first step.
The safety of biologics was studied by the Brazilian Biologics Registry in, eleven hundred RA patients and almost six hundred SPA patients, and found that serious, infectious events were common and increased in those that took the TNF inhibitors within, a threefold increased risk of an SIE if you were on a TNF inhibitor. That's an adjusted IR of 2.96. Now, it stands to reason it would be elevated, people who are sicker and people who are more inflamed and need stronger biologics do have a higher risk of infection, and so again it's something we need to realize it's part and parcel of who we're treating here. But if you use a second TNF inhibitor in that same population, the risk of infection is still, serious infection is still elevated at one point five five with the second go around of a TNF inhibitor. Being ever vigilant is the way to safeguard against serious infections in patients on biologics.
Homocysteine and lupus was analyzed via, I guess, a meta analysis of many studies. Turns out there were 36 studies that have looked at this that compared almost three thousand lupus patients who were tested to 3,000 controls who were tested, and turns out that homocysteine levels were significantly elevated in lupus patients compared to healthy controls, and that elevation was predicted by age, disease duration, disease activity, and having a BMI of greater than twenty three. This is a Chinese study, so a BMI of greater than twenty three was obese and higher. And this clearly says that, you know, the collagen vascular disease, vascular disease that is lupus could be identified further or contributed to further by hyper homocystinemia and that may be something we should be looking for and treating in the future. The FDA this past week approved a new IV form of a non steroidal, in this case it was meloxicam, It's called Angeso, a n g j e s o.
It's for the treatment of moderate to severe pain in adults with arthritis. It's for short term use. It's based on three of phase two, I'm sorry, two phase three trials, and one phase three safety study. This joins a number of nonsteroidals that are on the market. I did a little bit of research on there and as you know, Ketrololac is an IV nonsteroidal, but there are IV forms of Indomethacin, Ibuprofen, there was an IV form of I think Vioxx back in the day, there's also an IV form of Diclofenac and now there's an IV form of Meloxicam.
A cross sectional study looked at the association of periodontal disease with rheumatoid arthritis. Again, has been shown before, but nonetheless interesting to note that periodontal disease is associated with both the presence of CCP, antibodies and that the severity of periodontal disease also has association with disease activity. This was a study of one hundred and thirty nine RA patients. There's a nice free open label, reopen read on the mechanism of action of methotrexate from the methotrexate guy himself, doctor Bruce Cronstein from NYU, where he goes over the many potential mechanisms underlying the effects of methotrexate, including adenosine release, nitric oxide, synthase, uncoupling, effects on NF kappa b, and an increase was called link RNA p 21, and that's a a non coding intergenic RNA p 21. You know, you can learn more about this by going to RheumNow Live.
Bruce is one of our featured speakers on how methotrexate works at RheumNow Live that you can register for now. And two more reports, bariatric surgery improves rheumatoid arthritis, know, have been other reports talking about weight loss and bariatric surgery specifically suggesting that may be associated with disease control. We do know that bariatric surgery and weight loss doesn't seem to reduce risk, although there are studies that say that being obese increases the risk of developing RA. This particular study mirrors a few others that could have gone before it. This was sixty five patients, with a BMI of about thirty eight, half of whom went on to receive bariatric surgery with drug therapy, other just drug therapy.
Those had the bariatric surgery plus pharmacotherapy had better disease control, their ACR 20 responses were seventy five versus fifty two in the non bariatric surgery group, their ACR 50 was thirty one versus twenty one percent. Other markers of activity including C Dye were improved. Again, weight loss is important and bariatric surgery could be the means by which you get control of patients who are difficult to control but yet obese. There's a nice report from the Swedish SCAPIS population study, this stands for the Swedish Cardiopulmonary BioImage study, and this study they found that hyperuricemia predisposed to coronary artery disease as measured by a calcium artery, score, a calcium, score that was, twice elevated in in in let's see actually the calc score and diabetes was twice as common, in in RA patients. Let me get this right.
Let me see here. Hyperuricemia was associated with diabetes and a calcium artery score, not rheumatoid arthritis. The diabetes and elevated scores, we do know that hyperuricemia is a toxin basically for the vasculature. Hyperuricemia and gout are associated with increased risk of cardiovascular events, cardiovascular disease. This just says that population elevations of hyperuricemia can give subclinical increases in those calcium artery scores which may predict future events in some people.
Twice as common in men than women. Women, it wasn't so significant. Men, it was highly significant. That's it for this week. Go to the website.
Read more about these interesting reports. Go to roomnow.live and register for our meeting coming up in two weeks. Next time.
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