The RheumNow Week In Review Methotrexate CIRT Study %285.25.18%29 Save
The RheumNow Week In Review Methotrexate CIRT Study %285.25.18%29 by Dr. Cush
Transcription
It's the 05/25/2018. This is the RheumNow we can review. Hi. I'm doctor Jack Cush, executive editor of rheumnow.com. This week in the news, we have good news for you bone mavens, you DEXA heads.
Exciting news. What does a DSMB, the data safety monitoring board, and why they're rising to the occasion? And what lupus will and what lupus won't do? This and more. At the top of the news, have lupus studies, one coming from Denmark, a very large population based study looked at the frequency of cutaneous lupus erythematosus.
You know, this is a unique subset that often doesn't get a lot of attention, doesn't often have, any drug indications or even dedicated studies, but yet it's highly important and the interface between rheumatologists and dermatologists on CLE is an important one. But what is the actual prevalence of this problem? Well, in Denmark, the prevalence they found to be two point seven four cases of CLE per 100,000 individuals with a female to male ratio of four to one. They say this was sort of under what they might have expected based on other estimates but this is what they came up with. More importantly, they did show that of the CLE population, this very large population that they come up with, the ten year risk of those people converting to systemic lupus, SLE, was only thirteen percent, but it did take ten years.
The total number was eight percent of all individuals, but the ten year risk was thirteen percent. Don't ask me how they did it. But nonetheless, it does say there is a a small subset of these people who will go on to develop lupus. This is more likely in women and more likely in those, not surprisingly, with subacute cutaneous lupus erythematosus, anti Rho positive, etcetera. So it might tell you something about maybe who you should look at more closely if they just have CLE.
Another interesting study comes from a registry of five zero nine women who have lupus and looked at what happened with their offspring. Specifically, do the offspring of lupus patients develop more autoimmune disease? Well, amongst the offspring there was, what, seven twenty children born to these five zero nine women. They compared it to a very large, control cohort and found that no, they did not have a higher rate systemic or rheumatic autoimmune disease, amongst the children. So that's good news and good news for you have to have to give counseling to your patients who have lupus.
New England Journal, this week actually had an interesting letter to the editor from a Japan, a group in Japan that looked at their Kawasaki population. Kawasaki is much more popular or much more common in Japan, I don't think it's popular but nonetheless they actually looked at their nineteen forty five patients and looked at the onset of Kawasaki based on the seasons. And they had some interesting findings basically if the child was under age four months that the majority of them, sixty percent or so, had their onset during summer and fall. However, for children who had the onset of Kawasaki's at 84 or seven years of age or more. The majority of those, sixty percent or so, had their onset during winter and spring.
This says something about the maybe this not just the seasonal nature of this but the role of infections and may be important in helping to develop preventative strategies, in the very young, and in children of middle age sort of like around six, seven, eight. Sandoz announced this week that they have, received a new similar approval for their biosimilar version of infliximab. This one is called Zessly. Very happy kind of name, Zessly. Approved by the European Commission, it will have the same approvals as does infliximab for rheumatoid arthritis, adult and pediatric Crohn's, adult and pediatric ulcerative colitis, AS, psoriatic arthritis, and plaque psoriasis.
Good news in The EU. Again, we have a number of biologics here in The United States, they're slow to get going, aren't they? But we'll see more of that in the future. An interesting study, looked at how to best study patients with scleroderma with regard to their lung disease. Many of us, you know, typically reflexively will order PFTs and DLCO and look at that DLCO as evidence of what may be going on in the interstitial lung spaces of our scleroderma patients, and use that as maybe a sign of whether they have active ILD or whether they're getting worse etc.
Turns out though that DLCO is not that useful to a parameter and that it's quite subject to variation and how it's done and when it's done and if you do it every day seven days in a row you won't get the same results. Some, lung experts, advocate more strongly for FVC and or which is forced vital capacity and or total lung capacity TLC. Well, this particular paper that's that you can look at, looks at all of these and shows evidence where forced vital capacity may be better than DLCO and others where DLCO looks as good as TLC and, FVC. So it really you know, you look at this and maybe you come away more confused than you started out with. I come away thinking you probably should look at all three, FVC, TLC, and DLCO.
I personally like FVC as being maybe the more predictive parameter. An interesting study comes from John Giles group and published in J. Rheum where they looked at the interventions necessary to get their RA patients vaccinated. So in their clinic of two twenty eight patients they looked and saw how many people were getting vaccinations and turns out as in most studies were very bad at getting this done. About half of patients are receiving vaccinations as they should for influenza in this particular case.
The rates of failure to vaccinate were higher in younger, those with more infrequent visits, those who had high disease activity measured by high ESR and those who had negative vaccine attitudes, what we might call vaccinates. I think that's what we call them, at least that's what I call them. They actually went about and had an intervention, a multimodal intervention that included email reminders, education, EMR alerts in the charts of patients as they came up, and they sort of this multimodal effort, they showed that their rate of the misinterventions which was forty seven percent prior to the intervention was reduced to only twenty three percent so a fifty percent improvement, in actually getting vaccines done, and I think that's quite commendable. This is something that we need to take responsibility for and maybe if you could implement this with your EMR, discuss this with your colleagues, go to education about this topic, maybe you'd have better rates of vaccination at least with regard influenza. An interesting study looked at the prothrombotic tendencies in rheumatoid arthritis.
It was a small study of 85 patients using something called ROTUM which is rotational thromboelastometry. Thromboelastometry sounds painful, but nonetheless has some predictive value and what they found in their 85 patient cohort was that RA patients were much more likely to be prothrombotic and more likely to therefore may be at risk for DVTs and PEs and VTE in general. Those who were at such risk were those who had, not surprisingly, higher deaths, CRP scores, higher CRP levels, and higher platelet counts. So again it tells us what we know that RA patients are at higher risk of, venous thromboembolic events, and one might could measure it in this, using this methodology seems a little complicated to me. Think knowing and worrying about it in your patients might be the more prudent activity.
The Data Safety Monitoring Board, DSMBs, I've been a part of them, they're very interesting groups, they only look at all the safety data, they get unblinded, data and they look at ways to show that the drug is both safe and sometimes even effective that that's the charge of the data monitoring committee. Regeneron had a study going on with its anti neurograft monoclonal antibody called fasinumab, a phase three trial that was underway but actually was halted by the, data monitoring committee when they came up with the data showing that in a study that was looking at the intervention in OA patients with OA of the hip or knee or low back, that they saw a difference in the outcomes according to dose. And so they halted the study that was ongoing. They're going back to the drawing board, problems were seen at one dose but not at other doses so it's likely they'll come back with other studies in the future and resume the investigation of this drug. Again, this seems to be very effective therapy but it gets sidetracked by bad outcomes and the bad outcomes have to do with the patients that they are studying, meaning these are patients with really severe osteoarthritis end stage disease.
In previous studies, anti nerve growth factor inhibitors led to more cases of accelerated OA, more hip and knee replacements, more Charcot joint like damage and that put those studies on hold until the FDA took took a look at it and said well clearly it's the fact that this is really bad, patients who are just progressing, and especially when you take pain out of the equation, and let them damage those joints a little bit more. So whether this kind of therapy will make it to the market remains to be seen but it is a significant advance and does merit further study and further worry about the safety. Another data safety monitoring committee was formed for the CIRT trial, C I R T, run by at Harvard by Paul Rittker. This is a trial that rheumatologists are very interested in. This is the trial of methotrexate, not in RA patients but in heart patients.
Patients who have a high risk of cardiovascular events are randomized to receive either methotrexate or placebo and they're looking at a composite cardiovascular outcome. A very large prospective trial, 7,000 patients, was halted recently because the Data Safety Monitoring Board, Data Monitoring Committee said we have enough data, we can make our decisions based on the four thousand seven hundred and eighty six patients enrolled. This is good news, that means that now they're going into analysis and they, Ricker has said that they might have the data presented in time for the November 2018 heart meetings which is around the same time as the ACR meeting so it'll be interesting to see if this gets play in the press or at the meetings either at the heart meetings or at the arthritis meetings. Stay tuned. As you know other interventions were successful with this regard meaning the CANTOS study looked at the utility of IL-one inhibition, canakinumab, patients who had again cardiovascular risk showed it did work, it showed that it also reduced the risk of cancer and lung cancer.
So again, anti inflammatory therapy in heart disease may become all the rage when this data becomes more clear and gets presented in an educational forum where and it gets peer reviewed and etc. RA patients have a twofold increased risk of fractures, we know this, a current paper in Arthritis Care and Research looks at this, and relates this to CCP levels and to, appendicular lean body mass. We know that body mass and, especially fat mass and whatnot but lean body mass is not fat mass and they looked at lean body mass they showed it is associated with higher BMD scores, not surprising. That's been shown before but what was sort of new about this particular study was that higher titers of CCP was associated with lower levels of BMD. You might have sort of surmised that but this is I think some of the first data to actually show that, and so I think that's important especially when it comes to femoral neck BMD.
A few last studies, the FDA approved week, denosumab for use in glucocorticoid induced osteoporosis, a major advance, in the osteoporosis world. As you know, heretofore for GIOP, we had to use either bisphosphonates or Forteo with their, particular limitations. This addition is a significant one. We need more data, and and, about this and about how to treat, especially men who have osteoporosis and GIOP, but this is a significant advance. Advance.
An interesting study comes, from, a Japanese cohort that looked at, a two year study of two seventy one patients who had MPO positive ANCA vasculitis. Turns out the two thirds of these patients had microscopic poly, polyangiitis. As you know, in Japan, microscopic polyangiitis is much more common than probably GPA, but in their study they showed some very interesting results that patients who were treated, NPO positive patients with, ANCA associated vasculitis who were treated, then seventy two percent the NPO positivity normalized and that when those patients were followed over time, those who had relapses, forty percent of them patients who had normalized their NPO antibodies later had a recurrence of NPO antibodies and that was associated with a higher risk of relapse, the odds ratio being greater than twenty six. So, this suggests that NPO antibody monitoring may be prudent in patients who have, NPO positive associated vasculitis, and microscopic polyangiitis.
Exciting news. What does a DSMB, the data safety monitoring board, and why they're rising to the occasion? And what lupus will and what lupus won't do? This and more. At the top of the news, have lupus studies, one coming from Denmark, a very large population based study looked at the frequency of cutaneous lupus erythematosus.
You know, this is a unique subset that often doesn't get a lot of attention, doesn't often have, any drug indications or even dedicated studies, but yet it's highly important and the interface between rheumatologists and dermatologists on CLE is an important one. But what is the actual prevalence of this problem? Well, in Denmark, the prevalence they found to be two point seven four cases of CLE per 100,000 individuals with a female to male ratio of four to one. They say this was sort of under what they might have expected based on other estimates but this is what they came up with. More importantly, they did show that of the CLE population, this very large population that they come up with, the ten year risk of those people converting to systemic lupus, SLE, was only thirteen percent, but it did take ten years.
The total number was eight percent of all individuals, but the ten year risk was thirteen percent. Don't ask me how they did it. But nonetheless, it does say there is a a small subset of these people who will go on to develop lupus. This is more likely in women and more likely in those, not surprisingly, with subacute cutaneous lupus erythematosus, anti Rho positive, etcetera. So it might tell you something about maybe who you should look at more closely if they just have CLE.
Another interesting study comes from a registry of five zero nine women who have lupus and looked at what happened with their offspring. Specifically, do the offspring of lupus patients develop more autoimmune disease? Well, amongst the offspring there was, what, seven twenty children born to these five zero nine women. They compared it to a very large, control cohort and found that no, they did not have a higher rate systemic or rheumatic autoimmune disease, amongst the children. So that's good news and good news for you have to have to give counseling to your patients who have lupus.
New England Journal, this week actually had an interesting letter to the editor from a Japan, a group in Japan that looked at their Kawasaki population. Kawasaki is much more popular or much more common in Japan, I don't think it's popular but nonetheless they actually looked at their nineteen forty five patients and looked at the onset of Kawasaki based on the seasons. And they had some interesting findings basically if the child was under age four months that the majority of them, sixty percent or so, had their onset during summer and fall. However, for children who had the onset of Kawasaki's at 84 or seven years of age or more. The majority of those, sixty percent or so, had their onset during winter and spring.
This says something about the maybe this not just the seasonal nature of this but the role of infections and may be important in helping to develop preventative strategies, in the very young, and in children of middle age sort of like around six, seven, eight. Sandoz announced this week that they have, received a new similar approval for their biosimilar version of infliximab. This one is called Zessly. Very happy kind of name, Zessly. Approved by the European Commission, it will have the same approvals as does infliximab for rheumatoid arthritis, adult and pediatric Crohn's, adult and pediatric ulcerative colitis, AS, psoriatic arthritis, and plaque psoriasis.
Good news in The EU. Again, we have a number of biologics here in The United States, they're slow to get going, aren't they? But we'll see more of that in the future. An interesting study, looked at how to best study patients with scleroderma with regard to their lung disease. Many of us, you know, typically reflexively will order PFTs and DLCO and look at that DLCO as evidence of what may be going on in the interstitial lung spaces of our scleroderma patients, and use that as maybe a sign of whether they have active ILD or whether they're getting worse etc.
Turns out though that DLCO is not that useful to a parameter and that it's quite subject to variation and how it's done and when it's done and if you do it every day seven days in a row you won't get the same results. Some, lung experts, advocate more strongly for FVC and or which is forced vital capacity and or total lung capacity TLC. Well, this particular paper that's that you can look at, looks at all of these and shows evidence where forced vital capacity may be better than DLCO and others where DLCO looks as good as TLC and, FVC. So it really you know, you look at this and maybe you come away more confused than you started out with. I come away thinking you probably should look at all three, FVC, TLC, and DLCO.
I personally like FVC as being maybe the more predictive parameter. An interesting study comes from John Giles group and published in J. Rheum where they looked at the interventions necessary to get their RA patients vaccinated. So in their clinic of two twenty eight patients they looked and saw how many people were getting vaccinations and turns out as in most studies were very bad at getting this done. About half of patients are receiving vaccinations as they should for influenza in this particular case.
The rates of failure to vaccinate were higher in younger, those with more infrequent visits, those who had high disease activity measured by high ESR and those who had negative vaccine attitudes, what we might call vaccinates. I think that's what we call them, at least that's what I call them. They actually went about and had an intervention, a multimodal intervention that included email reminders, education, EMR alerts in the charts of patients as they came up, and they sort of this multimodal effort, they showed that their rate of the misinterventions which was forty seven percent prior to the intervention was reduced to only twenty three percent so a fifty percent improvement, in actually getting vaccines done, and I think that's quite commendable. This is something that we need to take responsibility for and maybe if you could implement this with your EMR, discuss this with your colleagues, go to education about this topic, maybe you'd have better rates of vaccination at least with regard influenza. An interesting study looked at the prothrombotic tendencies in rheumatoid arthritis.
It was a small study of 85 patients using something called ROTUM which is rotational thromboelastometry. Thromboelastometry sounds painful, but nonetheless has some predictive value and what they found in their 85 patient cohort was that RA patients were much more likely to be prothrombotic and more likely to therefore may be at risk for DVTs and PEs and VTE in general. Those who were at such risk were those who had, not surprisingly, higher deaths, CRP scores, higher CRP levels, and higher platelet counts. So again it tells us what we know that RA patients are at higher risk of, venous thromboembolic events, and one might could measure it in this, using this methodology seems a little complicated to me. Think knowing and worrying about it in your patients might be the more prudent activity.
The Data Safety Monitoring Board, DSMBs, I've been a part of them, they're very interesting groups, they only look at all the safety data, they get unblinded, data and they look at ways to show that the drug is both safe and sometimes even effective that that's the charge of the data monitoring committee. Regeneron had a study going on with its anti neurograft monoclonal antibody called fasinumab, a phase three trial that was underway but actually was halted by the, data monitoring committee when they came up with the data showing that in a study that was looking at the intervention in OA patients with OA of the hip or knee or low back, that they saw a difference in the outcomes according to dose. And so they halted the study that was ongoing. They're going back to the drawing board, problems were seen at one dose but not at other doses so it's likely they'll come back with other studies in the future and resume the investigation of this drug. Again, this seems to be very effective therapy but it gets sidetracked by bad outcomes and the bad outcomes have to do with the patients that they are studying, meaning these are patients with really severe osteoarthritis end stage disease.
In previous studies, anti nerve growth factor inhibitors led to more cases of accelerated OA, more hip and knee replacements, more Charcot joint like damage and that put those studies on hold until the FDA took took a look at it and said well clearly it's the fact that this is really bad, patients who are just progressing, and especially when you take pain out of the equation, and let them damage those joints a little bit more. So whether this kind of therapy will make it to the market remains to be seen but it is a significant advance and does merit further study and further worry about the safety. Another data safety monitoring committee was formed for the CIRT trial, C I R T, run by at Harvard by Paul Rittker. This is a trial that rheumatologists are very interested in. This is the trial of methotrexate, not in RA patients but in heart patients.
Patients who have a high risk of cardiovascular events are randomized to receive either methotrexate or placebo and they're looking at a composite cardiovascular outcome. A very large prospective trial, 7,000 patients, was halted recently because the Data Safety Monitoring Board, Data Monitoring Committee said we have enough data, we can make our decisions based on the four thousand seven hundred and eighty six patients enrolled. This is good news, that means that now they're going into analysis and they, Ricker has said that they might have the data presented in time for the November 2018 heart meetings which is around the same time as the ACR meeting so it'll be interesting to see if this gets play in the press or at the meetings either at the heart meetings or at the arthritis meetings. Stay tuned. As you know other interventions were successful with this regard meaning the CANTOS study looked at the utility of IL-one inhibition, canakinumab, patients who had again cardiovascular risk showed it did work, it showed that it also reduced the risk of cancer and lung cancer.
So again, anti inflammatory therapy in heart disease may become all the rage when this data becomes more clear and gets presented in an educational forum where and it gets peer reviewed and etc. RA patients have a twofold increased risk of fractures, we know this, a current paper in Arthritis Care and Research looks at this, and relates this to CCP levels and to, appendicular lean body mass. We know that body mass and, especially fat mass and whatnot but lean body mass is not fat mass and they looked at lean body mass they showed it is associated with higher BMD scores, not surprising. That's been shown before but what was sort of new about this particular study was that higher titers of CCP was associated with lower levels of BMD. You might have sort of surmised that but this is I think some of the first data to actually show that, and so I think that's important especially when it comes to femoral neck BMD.
A few last studies, the FDA approved week, denosumab for use in glucocorticoid induced osteoporosis, a major advance, in the osteoporosis world. As you know, heretofore for GIOP, we had to use either bisphosphonates or Forteo with their, particular limitations. This addition is a significant one. We need more data, and and, about this and about how to treat, especially men who have osteoporosis and GIOP, but this is a significant advance. Advance.
An interesting study comes, from, a Japanese cohort that looked at, a two year study of two seventy one patients who had MPO positive ANCA vasculitis. Turns out the two thirds of these patients had microscopic poly, polyangiitis. As you know, in Japan, microscopic polyangiitis is much more common than probably GPA, but in their study they showed some very interesting results that patients who were treated, NPO positive patients with, ANCA associated vasculitis who were treated, then seventy two percent the NPO positivity normalized and that when those patients were followed over time, those who had relapses, forty percent of them patients who had normalized their NPO antibodies later had a recurrence of NPO antibodies and that was associated with a higher risk of relapse, the odds ratio being greater than twenty six. So, this suggests that NPO antibody monitoring may be prudent in patients who have, NPO positive associated vasculitis, and microscopic polyangiitis.
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