The RheumNow Week in Review May 26, 2017 Save
The RheumNow Week in Review May 26, 2017 by Dr. Cush
Transcription
Hey now. I'm Jack Cush, executive editor of rheumnow.com. This is the 05/26/2017, and you're listening to the RheumNow weekend review. Highlights in the news this week is IL-six is a hot topic, especially as far as new regulatory approvals. Additionally, a major new osteoporosis drug in development may have hit the skids for heart reasons.
More on those later. At the top of the news, an interesting study done with twenty four patients with erosive RA looked to see if whether you could use an anabolic steroid teriparatide to prevent the development of erosions. In this one year study, headed by Dan Solomon and Ellen Gravelis, they actually did not show that the use of the anabolic steroid, provided any, reduction in either the rate or the volume of erosions that were seen in the twenty four patients that were treated. There have been some studies in the past that looked at bisphosphonates as potential add ons to reduce or Prolia for that matter, again, with some variable results. While it makes some sense to make this approach in an erosive disease, it seems better to control the disease with inflammation, and that's where anti TNF inhibitors have been particularly effective.
Interesting study comes out of Sweden. A large cohort study, a nationwide study of patients with, ankylosing spondylitis, psoriatic arthritis, and undifferentiated spondyloarthropathy looked at over twenty seven thousand patients, compared them almost five to one to a normal control population, and looked at the rate of acute coronary syndrome and strokes. In fact, they showed, higher rates of acute coronary syndrome and stroke in patients who had these inflammatory disorders. Not surprising, as we know that inflammation does drive cardiovascular risk in rheumatoid arthritis and some other disorders, and this has been seen before, but what's good about this study is it comes from a very reputable group, very large cohort study, very well done research, again underscores the importance of controlling inflammation to control the untoward effects of inflammation. A nice study looked at potential biomarker for IL-seventeen driven psoriasis.
We know, interleukin-seventeen is very important in the pathogenesis of psoriasis. What drives that, however, is not known. IL-seventeen is very much involved in defense mechanisms and mucosal, immunity and whatnot, and in this particular study they looked at, eight patients with and without psoriasis, and they analyzed, 170 or more proteins from the skin, both lesional and non lesional skin, and from blood, and to see what might correlate with IL-seventeen or, markers of disease activity. And they found that beta defensin-two was really quite a good biomarker. Number one, it's fairly easy to measure and, and seemed to have a high correlation with Posse Skin scores and also in IL-17A levels.
So, again, this represents a potentially useful biomarker for the future. The TYCOPA study is a tight control in psoriasis and psoriatic arthritis trial that, showed that, as it did in RA, the tight control and aggressive therapy had certain benefits. However, a new financial analysis looked at the cost effectiveness of tight control, specifically they looked at quality adjusted life years and showed that, tight control was more costly, almost twice as much more costly, and also had a significant increase in QALYs, but was not necessarily cost effective in, most analyses that they ran. What they did see, however, was that certain subsets of aggressive patients, might make some sense to use a more aggressive regimen as was done in Tycoppa. So, sort of bad news that, sometimes using more expensive therapies isn't always the best or most cost effective measure.
A very interesting study looked at the infection rate in children with JIA who go on biologics. Specifically, they looked at serious bacterial infections. In a study of two thousand four hundred and ninety five JIA patients, they showed and this is claims data that there was a much higher rate of serious bacterial infections in those who were taking TNF inhibitors versus those who were just taking DMARDs. Now, could be some selection bias here, obviously sicker patients are going to get a TNF inhibitor, but nonetheless, it is something that's usually not been seen in other studies, that again, it is a significant increase in SIEs, and that, you know, it's something that might be a true message, especially in children who have, just pure inflammatory disease and haven't been on a lot of other therapies. So, a little bit of warning there.
A study of patients who have, ANCA associated vasculitis, three twenty three patients, and compared what the subsequent cancer rate might be if they were treated with Citoxan or Rituxan. And, we know from other studies that, such patients may be at higher rate of certain cancers, especially if they receive cyclophosphamide where there's a high rate of urogenital cancers, bladder cancers. And in this particular study, they showed that the cancer rate was higher, with an SIR of a standardized incidence ratio of three point one for cytotoxin, and that was four and a half full higher rates of cancer compared to Rituxan. So the significant risk with cytotoxin, 3.1 SIR versus 0.67 SIR with Rituxan. In Rituxan, they found that the cancer rate was roughly equal to the population rate.
So obviously, there's a significant risk to using Citoxan or cyclophosphamide in patients with ANCA associated vasculitis. The two big, bits of news from the regulatory front this week from the FDA, on the same day the FDA approved the use of Kevzara, the generic name being cerulimab, an IL-six inhibitor, and this now becomes the second FDA approved IL-six inhibitor for use in patients with active rheumatoid arthritis. Kevzara has been approved in Canada and other countries, and the interesting thing about this drug that's being, developed by Regeneron and Sanofi is that it comes into the market priced 30% below the current TNF inhibitor price, which is roughly around 49 and $50,000. This comes in at $39,000, so aggressive pricing for a brand new product, IL-six inhibitors are going to expand. We now have, obviously, Actemra and now Kevzara in the market, and there's another one soon to follow.
Speaking of Actemra or tocilizumab, the FDA approved this week Actemra for use in patients who have giant cell arteritis. Really based on the GIACTA study, this drug was sort of given a fast track to FDA approval, was approved the as a subcutaneous administered drug, and it says in the package insert that it should be given, along with tapering doses of corticosteroids. So the idea of giving this drug so that you can get patients off of their corticosteroids, as demonstrated in the trial, is also demonstrated or reflected in the package insert. The ACR has actually been very active. If you haven't noticed, under Sherrod Lock and Paul, they've had a lot of announcements about position statements, responses to what's going on with Trumpcare and whatnot.
The ACR issued another statement this week supporting the FDA's draft on interchangeability. They support the FDA's position on naming suffixes, meaning that infliximab is not just infliximab, it's also called infliximab, D D D D Y Y B for the new one, Inflectra, etcetera, so that we can distinguish between the generic infliximab and the biosimilar infliximab. And they also support the Biosimilar User Fee Act, which the FDA is considering, but they actually had a strange, but not expanded upon statement about extrapolation. They did not question the issue of extrapolation. Extrapolation being that if a drug is studied approved for studied in rheumatoid arthritis and gets approved as a biosimilar, it gets all the indications of the biosimilar that was or the originator was being compared to.
So you could do just a study in psoriasis yet get an indication for rheumatoid arthritis, JIA, Crohn's disease, and ulcerative colitis even though you didn't do those trials. That's extrapolation. And you may not like it, but that's the rule, and the rule is really based on if you prove biosimilarity, if you prove structural, chemical, functional, and mechanism of action, biosimilarity, through analytical methods, then all you need is one clinical trial to get the drug approved and then you get all the indications. So it's not something that's really up for debate and why they didn't approve it or have a problem with it. Worldwide, no one else is having a problem with it.
A survey in The UK of three sixty four patients looked at patient attitudes about how they receive information on TNF inhibitors and showed that a third of patients who got information about the new use of a biologic, a TNF inhibitor, said that openly it helps them, and another third said openly that it hurts them, meaning it scares them. So, you know, where's the fine line? There are many who have sort of misconstrued, impressions about biosimilars, about biologics, and their safety, especially their safety. But it is the idea that giving patients more information may in fact be a deterrent to, the use of the drug, filling the prescription, and being adherent. My overall rule is give the patient written material, to tell them to read, question, circle, and come back and not to make decisions without talking to me.
But I more specifically focus on three things that they can expect that are most common side effects. I also give them the one or two or three things that are the most dangerous that might avert their use and explain why that's a one in one thousand risk, and that's a low risk compared to the risk of the disease that they're trying to treat. Last week I was at a state society meeting in Puerto Rico and Doctor. Doric Erkan was there talking, about, antiphospholipid syndrome. He's an expert from Hospital for Special Surgery and, I came up with two pearls, one that in treating, secondary thrombosis prevention, the current management of those venous thrombosis would be to use warfarin and keep the INR between two and three for the venous thrombosis, but that if you're treating arterial thrombosis that you really wanna keep the INR between, what does it say, two and three, but also use aspirin.
If you're not gonna use aspirin and you're dealing with arterial thrombosis, you probably should keep the INR between three and four. So, again, that's venous thrombosis. It's without aspirin. It's two and three is the INR with Coumadin. But if it's arterial thrombosis, use aspirin and same INR of two to three is is suggested.
But if you're not gonna use aspirin, can't use aspirin, you need a higher INR three to four. He also came across with the management of catastrophic antiphospholipid syndrome currently is anticoagulation, high dose steroids, IVIG, often with plasma exchange, and there's some suggestion that some patients might even benefit from the use of rituximab. An important development in the news came this week with the announcement by Amgen and UCB about their drug Romelosizumab, is also called Evenity, e v e n I t y. This is an antisclerostin drug that has a great deal of promise in the treatment of osteoporosis and strengthening bones, they've had a number of phase two, three trials that looked very good, highly promising in their ability to reduce fracture rates, overall, but, they announced the results of the ARCH trial and what was unique about this trial was one, it's design, it was Romecizumab given for twelve months followed by alendronate and then a matched placebo control who didn't get Romecizumab who took alendronate, and they showed there was a significant reduction in both vertebral and non vertebral fractures at the end of twenty four months. The problem was at the at the end, they also noticed an imbalance in cardiac events, the nature of which is not disclosed.
It was it was it was reported that two point five percent of those on Romecizumab, had these cardiac events versus only one point nine in the alendronate only group, suggesting this could be a potential problem. So there's a lot of buzz about this. This could lead to a stall in the drug's development or its approval or could lead to an FDA hearing. Still a lot of unknowns but a drug that was previously thought to be fast tracked for approval and success now has a wrinkle in or a bump in the road, let's say, in its development. And lastly, it was an important report, from, The New England Journal on the use of, an anti IL-five monoclonal antibody called meplizumab, and it was used in patients who have Churg Strauss vasculitis, now called eosinophilic granulomatosis with polyangiitis or EGPA.
In this particular study reported in New England Journal, a hundred thirty six patients with relapsing or recurrent disease were given either placebo or three hundred milligrams of meplizumab every four weeks. And in the end, that the patients who received the anti IL-five monoclonal antibody had a higher percentage of remissions, at forty eight weeks, thirty two percent versus three percent, and the number of patients who did not achieve remission was much lower on meplizumab, forty seven percent versus eighty one percent. The interesting thing about this is when this drug worked, it worked on the components that might be IL-five driven, meaning, the asthma symptoms and the sinusitis, nasal symptoms, not as much on the vasculitis symptoms. So this drug needs to be studied, with maybe in combination with other drugs that are better at vasculitis, and it's unclear, although it's very promising, it's unclear exactly who should get this drug going forward in the future. And one more lastly, I have, actually a report about, Still's disease, my favorite disorder.
This is a study of thirty four patients with adult onset Still's disease and looked at the association of Still's disease with the NLRP3 gene that is important in activation of the inflammasome which drives the systemic inflammatory disorder. While everyone assumes that Still's disease is an autoinflammatory syndrome based on its responsiveness to IL-one inhibition and the symptomatology, which is very akin to that seen with all the other autoinflammatory syndromes, the direct connection with activation of the NLRP3 gene and the inflammasome hasn't been well demonstrated. So, in this particular study, they looked at 34 patients and controls, and they showed that there was significantly higher degree of mRNA expression of the NLRP3 gene compared to controls and much higher. Moreover, NLRP3 mRNA levels correlated highly with, Still's disease activity measures. They did further experiments that looked at what happens if you activate, the gene with a TLR7, ligand, and they showed that if you can activate NLRP3, in these patients, in their PBMs, that you actually have even higher levels of NLRP3 expression and if you can inhibit it, you have even lower levels also done in the same patients.
All of which is to say it's a fairly good connection here that says the NLRP3 gene is activated, turned on, and is probably driving patients with Still's disease. We do not know what the instigators are of that process and it's obviously not genetically based as are many of the other auto inflammatory syndromes which are monogenic, often appearing early life. This is an acquired or, a developmental, defect that occurs that leads to this periodic fever called adult onset Still's disease. That's it for this week at roomnow.com. Go to the website to see, all these citations and more.
Tune in next week for more news from roomnow.com.
More on those later. At the top of the news, an interesting study done with twenty four patients with erosive RA looked to see if whether you could use an anabolic steroid teriparatide to prevent the development of erosions. In this one year study, headed by Dan Solomon and Ellen Gravelis, they actually did not show that the use of the anabolic steroid, provided any, reduction in either the rate or the volume of erosions that were seen in the twenty four patients that were treated. There have been some studies in the past that looked at bisphosphonates as potential add ons to reduce or Prolia for that matter, again, with some variable results. While it makes some sense to make this approach in an erosive disease, it seems better to control the disease with inflammation, and that's where anti TNF inhibitors have been particularly effective.
Interesting study comes out of Sweden. A large cohort study, a nationwide study of patients with, ankylosing spondylitis, psoriatic arthritis, and undifferentiated spondyloarthropathy looked at over twenty seven thousand patients, compared them almost five to one to a normal control population, and looked at the rate of acute coronary syndrome and strokes. In fact, they showed, higher rates of acute coronary syndrome and stroke in patients who had these inflammatory disorders. Not surprising, as we know that inflammation does drive cardiovascular risk in rheumatoid arthritis and some other disorders, and this has been seen before, but what's good about this study is it comes from a very reputable group, very large cohort study, very well done research, again underscores the importance of controlling inflammation to control the untoward effects of inflammation. A nice study looked at potential biomarker for IL-seventeen driven psoriasis.
We know, interleukin-seventeen is very important in the pathogenesis of psoriasis. What drives that, however, is not known. IL-seventeen is very much involved in defense mechanisms and mucosal, immunity and whatnot, and in this particular study they looked at, eight patients with and without psoriasis, and they analyzed, 170 or more proteins from the skin, both lesional and non lesional skin, and from blood, and to see what might correlate with IL-seventeen or, markers of disease activity. And they found that beta defensin-two was really quite a good biomarker. Number one, it's fairly easy to measure and, and seemed to have a high correlation with Posse Skin scores and also in IL-17A levels.
So, again, this represents a potentially useful biomarker for the future. The TYCOPA study is a tight control in psoriasis and psoriatic arthritis trial that, showed that, as it did in RA, the tight control and aggressive therapy had certain benefits. However, a new financial analysis looked at the cost effectiveness of tight control, specifically they looked at quality adjusted life years and showed that, tight control was more costly, almost twice as much more costly, and also had a significant increase in QALYs, but was not necessarily cost effective in, most analyses that they ran. What they did see, however, was that certain subsets of aggressive patients, might make some sense to use a more aggressive regimen as was done in Tycoppa. So, sort of bad news that, sometimes using more expensive therapies isn't always the best or most cost effective measure.
A very interesting study looked at the infection rate in children with JIA who go on biologics. Specifically, they looked at serious bacterial infections. In a study of two thousand four hundred and ninety five JIA patients, they showed and this is claims data that there was a much higher rate of serious bacterial infections in those who were taking TNF inhibitors versus those who were just taking DMARDs. Now, could be some selection bias here, obviously sicker patients are going to get a TNF inhibitor, but nonetheless, it is something that's usually not been seen in other studies, that again, it is a significant increase in SIEs, and that, you know, it's something that might be a true message, especially in children who have, just pure inflammatory disease and haven't been on a lot of other therapies. So, a little bit of warning there.
A study of patients who have, ANCA associated vasculitis, three twenty three patients, and compared what the subsequent cancer rate might be if they were treated with Citoxan or Rituxan. And, we know from other studies that, such patients may be at higher rate of certain cancers, especially if they receive cyclophosphamide where there's a high rate of urogenital cancers, bladder cancers. And in this particular study, they showed that the cancer rate was higher, with an SIR of a standardized incidence ratio of three point one for cytotoxin, and that was four and a half full higher rates of cancer compared to Rituxan. So the significant risk with cytotoxin, 3.1 SIR versus 0.67 SIR with Rituxan. In Rituxan, they found that the cancer rate was roughly equal to the population rate.
So obviously, there's a significant risk to using Citoxan or cyclophosphamide in patients with ANCA associated vasculitis. The two big, bits of news from the regulatory front this week from the FDA, on the same day the FDA approved the use of Kevzara, the generic name being cerulimab, an IL-six inhibitor, and this now becomes the second FDA approved IL-six inhibitor for use in patients with active rheumatoid arthritis. Kevzara has been approved in Canada and other countries, and the interesting thing about this drug that's being, developed by Regeneron and Sanofi is that it comes into the market priced 30% below the current TNF inhibitor price, which is roughly around 49 and $50,000. This comes in at $39,000, so aggressive pricing for a brand new product, IL-six inhibitors are going to expand. We now have, obviously, Actemra and now Kevzara in the market, and there's another one soon to follow.
Speaking of Actemra or tocilizumab, the FDA approved this week Actemra for use in patients who have giant cell arteritis. Really based on the GIACTA study, this drug was sort of given a fast track to FDA approval, was approved the as a subcutaneous administered drug, and it says in the package insert that it should be given, along with tapering doses of corticosteroids. So the idea of giving this drug so that you can get patients off of their corticosteroids, as demonstrated in the trial, is also demonstrated or reflected in the package insert. The ACR has actually been very active. If you haven't noticed, under Sherrod Lock and Paul, they've had a lot of announcements about position statements, responses to what's going on with Trumpcare and whatnot.
The ACR issued another statement this week supporting the FDA's draft on interchangeability. They support the FDA's position on naming suffixes, meaning that infliximab is not just infliximab, it's also called infliximab, D D D D Y Y B for the new one, Inflectra, etcetera, so that we can distinguish between the generic infliximab and the biosimilar infliximab. And they also support the Biosimilar User Fee Act, which the FDA is considering, but they actually had a strange, but not expanded upon statement about extrapolation. They did not question the issue of extrapolation. Extrapolation being that if a drug is studied approved for studied in rheumatoid arthritis and gets approved as a biosimilar, it gets all the indications of the biosimilar that was or the originator was being compared to.
So you could do just a study in psoriasis yet get an indication for rheumatoid arthritis, JIA, Crohn's disease, and ulcerative colitis even though you didn't do those trials. That's extrapolation. And you may not like it, but that's the rule, and the rule is really based on if you prove biosimilarity, if you prove structural, chemical, functional, and mechanism of action, biosimilarity, through analytical methods, then all you need is one clinical trial to get the drug approved and then you get all the indications. So it's not something that's really up for debate and why they didn't approve it or have a problem with it. Worldwide, no one else is having a problem with it.
A survey in The UK of three sixty four patients looked at patient attitudes about how they receive information on TNF inhibitors and showed that a third of patients who got information about the new use of a biologic, a TNF inhibitor, said that openly it helps them, and another third said openly that it hurts them, meaning it scares them. So, you know, where's the fine line? There are many who have sort of misconstrued, impressions about biosimilars, about biologics, and their safety, especially their safety. But it is the idea that giving patients more information may in fact be a deterrent to, the use of the drug, filling the prescription, and being adherent. My overall rule is give the patient written material, to tell them to read, question, circle, and come back and not to make decisions without talking to me.
But I more specifically focus on three things that they can expect that are most common side effects. I also give them the one or two or three things that are the most dangerous that might avert their use and explain why that's a one in one thousand risk, and that's a low risk compared to the risk of the disease that they're trying to treat. Last week I was at a state society meeting in Puerto Rico and Doctor. Doric Erkan was there talking, about, antiphospholipid syndrome. He's an expert from Hospital for Special Surgery and, I came up with two pearls, one that in treating, secondary thrombosis prevention, the current management of those venous thrombosis would be to use warfarin and keep the INR between two and three for the venous thrombosis, but that if you're treating arterial thrombosis that you really wanna keep the INR between, what does it say, two and three, but also use aspirin.
If you're not gonna use aspirin and you're dealing with arterial thrombosis, you probably should keep the INR between three and four. So, again, that's venous thrombosis. It's without aspirin. It's two and three is the INR with Coumadin. But if it's arterial thrombosis, use aspirin and same INR of two to three is is suggested.
But if you're not gonna use aspirin, can't use aspirin, you need a higher INR three to four. He also came across with the management of catastrophic antiphospholipid syndrome currently is anticoagulation, high dose steroids, IVIG, often with plasma exchange, and there's some suggestion that some patients might even benefit from the use of rituximab. An important development in the news came this week with the announcement by Amgen and UCB about their drug Romelosizumab, is also called Evenity, e v e n I t y. This is an antisclerostin drug that has a great deal of promise in the treatment of osteoporosis and strengthening bones, they've had a number of phase two, three trials that looked very good, highly promising in their ability to reduce fracture rates, overall, but, they announced the results of the ARCH trial and what was unique about this trial was one, it's design, it was Romecizumab given for twelve months followed by alendronate and then a matched placebo control who didn't get Romecizumab who took alendronate, and they showed there was a significant reduction in both vertebral and non vertebral fractures at the end of twenty four months. The problem was at the at the end, they also noticed an imbalance in cardiac events, the nature of which is not disclosed.
It was it was it was reported that two point five percent of those on Romecizumab, had these cardiac events versus only one point nine in the alendronate only group, suggesting this could be a potential problem. So there's a lot of buzz about this. This could lead to a stall in the drug's development or its approval or could lead to an FDA hearing. Still a lot of unknowns but a drug that was previously thought to be fast tracked for approval and success now has a wrinkle in or a bump in the road, let's say, in its development. And lastly, it was an important report, from, The New England Journal on the use of, an anti IL-five monoclonal antibody called meplizumab, and it was used in patients who have Churg Strauss vasculitis, now called eosinophilic granulomatosis with polyangiitis or EGPA.
In this particular study reported in New England Journal, a hundred thirty six patients with relapsing or recurrent disease were given either placebo or three hundred milligrams of meplizumab every four weeks. And in the end, that the patients who received the anti IL-five monoclonal antibody had a higher percentage of remissions, at forty eight weeks, thirty two percent versus three percent, and the number of patients who did not achieve remission was much lower on meplizumab, forty seven percent versus eighty one percent. The interesting thing about this is when this drug worked, it worked on the components that might be IL-five driven, meaning, the asthma symptoms and the sinusitis, nasal symptoms, not as much on the vasculitis symptoms. So this drug needs to be studied, with maybe in combination with other drugs that are better at vasculitis, and it's unclear, although it's very promising, it's unclear exactly who should get this drug going forward in the future. And one more lastly, I have, actually a report about, Still's disease, my favorite disorder.
This is a study of thirty four patients with adult onset Still's disease and looked at the association of Still's disease with the NLRP3 gene that is important in activation of the inflammasome which drives the systemic inflammatory disorder. While everyone assumes that Still's disease is an autoinflammatory syndrome based on its responsiveness to IL-one inhibition and the symptomatology, which is very akin to that seen with all the other autoinflammatory syndromes, the direct connection with activation of the NLRP3 gene and the inflammasome hasn't been well demonstrated. So, in this particular study, they looked at 34 patients and controls, and they showed that there was significantly higher degree of mRNA expression of the NLRP3 gene compared to controls and much higher. Moreover, NLRP3 mRNA levels correlated highly with, Still's disease activity measures. They did further experiments that looked at what happens if you activate, the gene with a TLR7, ligand, and they showed that if you can activate NLRP3, in these patients, in their PBMs, that you actually have even higher levels of NLRP3 expression and if you can inhibit it, you have even lower levels also done in the same patients.
All of which is to say it's a fairly good connection here that says the NLRP3 gene is activated, turned on, and is probably driving patients with Still's disease. We do not know what the instigators are of that process and it's obviously not genetically based as are many of the other auto inflammatory syndromes which are monogenic, often appearing early life. This is an acquired or, a developmental, defect that occurs that leads to this periodic fever called adult onset Still's disease. That's it for this week at roomnow.com. Go to the website to see, all these citations and more.
Tune in next week for more news from roomnow.com.
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