The RheumNow Week In Review - 16 March 2018 Save
The RheumNow Week In Review - 16 March 2018 by Dr. Cush
Transcription
It's the 03/16/2018, and this is a RheumNow we can review. Hi. I'm doctor Jack Cush, executive editor of roomnow.com. And this week, have big time rheumatology lessons from tales from the crypts, the intestinal crypts, the friendly skies, and of all things, the hips of hockey players. This week in the news we have talk of drug induced syndromes.
I don't know about you, but during my training, induced lupus was sort of a big deal. There's a lot of talk about it, there were some cases of it. It's kind of exciting when you saw it, when you talked about it, when you learned about it. Haven't seen a good case of drug induced lupus in many, many years, but what we have heard a lot about in the last year are these immune related adverse events associated with checkpoint inhibitors, these new miracle magical drugs in cancer. Well, there's yet another report in the literature this week on a meta analysis of several of these drugs, novelimumab, pembrolizumab, pembrolizumab, and atezolizumab.
It's even hard for rheumatologists to talk about new mAbs. But anyway, when they reviewed the existing literature that's out there, they showed what the predominance was as far as these immune related adverse events that have an autoimmune nature. At the top of the list actually is hypothyroidism with an eightfold increased risk. Next is pneumonitis with a fivefold increased risk, colitis with a threefold increased risk, hypophysitis, not something we usually talk about, but it's very common with this syndrome, and three point fourfold increased risk in rash, a double risk, in these people. Also leading the way as far as symptoms that are commonly seen in these patients are fatigue, diarrhea in twenty percent, and probably around twenty percent or more of our patients that, will present to us will present because of arthralgia or back pain associated with the checkpoint inhibitors.
It's a nice review, you can look at that to find out more information. Again, we have a lot on the website about this topic. From science this week is a very interesting discussion on the Pathobion Enterococcus gallinarum. What is a pathobiont? A pathobiont, no, it's not a faculty member that you're working with.
It is a normal microbe that lives in symbiosis, but under certain circumstances can become pathologic. In this case, the, gut microbe Enterococcus gallinarum in certain situations just lives in the gut, but it has the ability to become invasive and in certain, or in certain genetic backgrounds may lead to autoimmunity. In this particular study, they actually showed that the enterococcus does lead and they use a mouse model for this. They looked at and they specifically use a mouse model that has a genetic predisposition to lupus and autoimmunity. When They were, colonnaded with enterococcus gallinearum, they actually had tissue invasion and that led to, pathogenic autoantibodies and Treg cells and really the onset of what was an autoimmune syndrome, not quite lupus, the way they played it out.
The same bug has been associated with autoimmune hepatitis in animal models. More interestingly, in this particular report, they showed that if you treat the animals that have been infected with vancomycin, you can prevent mortality and autoimmunity by suppressing the growth of E. Galanarum and eliminating those pathogenic autoantibodies and T cells. So it's a nice model whereby the microbiome becomes disorder disrupted in someone who are in a species that may have a risk for lupus like disease. This follows well on the coattails of the report that was done at ACR by Greg Silverman showing you some of the microbiome changes that may be associated with lupus and specifically with lupus nephritis.
You can find that on the website. There was a nice video by Greg, on our website that you can look at. A new study about GPA shows in Italy, they studied a cohort of 89 patients and specifically looked at it was a much larger cohort of GPA patients, but specifically they looked at eighty nine patients who had ENT involvement. They found ENT involvement in seventy two percent of their patients. Such patients who had ENT, GPA tended to be younger, They tended to have less renal disease.
Important because you don't want renal disease with GPA. The most dominant, of the ENT symptoms were sino nasal symptoms seen in almost sixty percent of patients and of the otic manifestations, thirty five percent either had otitis media or otomastoiditis. Overall, it turns out that ENT involvement predicted better outcomes with GPA, milder disease, a lower overall risk of renal disease, and overall better mortality. Something to be hopeful for when managing and seeing patients with GPA. An interesting study comes from Glasgow.
This is a study that was actually just reported this past week at the American Academy of Orthopedic Surgery meeting. This is a study that comes from the Golden Jubilee National Hospital in Glasgow where they studied the impact of how patients following their lower limb arthroplasty, hip or knee arthroplasty, how they traveled when they came for their follow-up visits to the National Hospital. They looked at patients who traveled by land and I assume that means trains and cars and whatnot, and versus those who traveled by plane. Since it was Glasgow, the trips weren't that long. The average time was only about seventy two minutes in the air and then such patients had on average six such flights.
But when they looked at the overall numbers, and again, all these people post operatively were, being, prophylaxed with anticoagulants of some sort. Despite them all being treated the same, the introduction of air travel, increased the odds of developing a venous thromboembolic event. So they looked at both PEs and DVTs, and the overall rate for those that were traveling by land was zero point five eight percent. The rate for those who traveled by air was one point six five percent, almost a threefold increase in the risk of VTEs, in patients who had lower limb arthroplasties, followed in Glasgow. This is one of the first studies that actually showed us.
The question is, what are you going to do about it? The website I wrote, I, had bilateral knee replacements, I usually wear compression stockings when I'm going be on a flight that's any more than an hour. Now the utility of that is really not known, but I think that the idea of instructing your patients to maybe have some protective measures, there are a lot of things you can do, getting up and walking around, exercises, maybe even using anticoagulants for short term use, these should be considered until really good data comes along. Because one of the hazardous, most hazardous outcomes in patients with knee or hip replacement is the complication of a venous thromboembolic event. A nice study comes from the BSRBR, the British Biologics Registry, almost 20,000 patients follow for over one hundred and six thousand patient years, meaning these patients were roughly followed for more than five years of follow-up.
And they looked at the incidence of opportunistic infections, in this cohort. They found and it specifically excluded patients with TB. And what they did find was that, overall, their rate of opportunistic infections was a hundred and thirty four per hundred thousand or to put it in a number you might understand better is one point three per one thousand patient years. Again, that's a number I keep bringing up in other reports that these very rare events that people are very, very concerned about still have about a one in one thousand risks. That is the risk of an opportunistic infection in RA patients going on biologics.
Interestingly, they showed that excluding TB, there's no real difference in the rate of opportunistic infections when you look at the different biologic classes, TNF inhibitors, IL-six inhibitors, etc. Across the board, they're really about the same. The only differences were a few, that pneumocystis, urovecai infections were higher with rituximab compared to TNF inhibitors, and that rituximab patients actually had a lower rate of TB compared to the TNF inhibitors. And maybe the most dramatic is the dramatic fall in TB events. In 2002, the rate of TB events was seven eighty three per one hundred thousand and it dropped to thirty eight by twenty fifteen per one hundred thousand.
Now, the population rate in United States and The UK is about four to five per one hundred thousand for just TB. So these rates are still elevated even in 2015 at thirty eight, but it's certainly down dramatically compared to that in 2002. Speaks a lot for your current practices of screening, and making sure patients don't have TB prior to the initiation of such therapy. There's an interesting report that finally appeared in the literature that was covered in great depth at the ACR meeting and really raised the number of eyebrows and that is the finding of bone marrow edema in elite athletes. When you're looking at the SI joints and specifically these investigators looked at 20 recreational runners and 22 professional ice hockey players, and they made them exercise through a vigorous routine and they had, before and after, MRIs.
And specifically, they were looking for evidence of sacroiliitis as measured by bone marrow edema, one of the criteria, by ASAS, the organization that's made criteria for the study of patients with spondylitis. Overall, these elite athletes, these active athletes found a rate of thirty to forty one percent who had new bone marrow lesions, bone marrow edema following their exercise, suggesting that this may not be as specific a finding, and that its, utility may be questioned. What they didn't find in these people were erosive changes and that may be the distinguishing feature between patients who have axial spondyloarthritis and athletes or people who are involved in vigorous exercise. Plaquenil, we know is vitamin P for all our patients with lupus. The study comes from, the Alzheimer's Rheumatic Disease and the lupus, cohort followed, by Michelle Petrie and others, very large cohort.
The number was something like thirteen forty nine patients followed at the Hopkins Lupus Clinic longitudinally. What they looked at were the rates of flares in lupus patients prior to pregnancy, with pregnancy and in postpartum period. What they showed was that lupus patients have an increased rate of lupus flares during pregnancy. In fact, the fifty nine percent increase rate of flares. This is not surprising, but it's important number to know if you want to quote to your patients what the rate of flare, what the odds of flaring are.
Maybe more important from the study was that, being on Plaquenil dropped the rates of flare significantly. If you are not on Plaquenil, the hazard ratio of getting a flare during pregnancy was one point eight three, but if you were on Plaquenil, this dropped to one point two six. Again, further evidence that it's wise to continue hydroxychloroquine throughout the pregnancy in your lupus patients. Lastly, there's a study from the New England Journal that's published just yesterday, the CARE study. This was published both in several journals and comes out from the cardiology national meeting that's going on.
This is a study of six thousand one hundred ninety gout patients who have a history of cardiovascular disease and therefore at high risk for cardiovascular events. They're specifically looking at the development of a cardiovascular endpoint in patients who are either taking febuxostat forty milligrams a day or allopurinol three hundred milligrams a day, and those patients were allowed to adjust the dose of their urate lowering therapy upwards to achieve a target serum urate less than six. The purpose of the study was to get to the number of six 20 four adjudicated cardiovascular events. The primary endpoint was a combination of cardiovascular death, nonfatal MI, nonfatal stroke, unstable angina with urgent revascularization. Turns out that the primary endpoint was not different in these patients who received one drug or the other.
They were followed for a median of thirty two months and as long as eighty four months. A lot of the patients were followed for five or six years. After thirty two months, start to see a difference between the fabuxtat group and the allopurinol group that the lines would start to diverge as far as developing some of these events. It turns out that the significant difference was found in cardiovascular death, which was thirty four percent higher in the febuxostat group, and all cause mortality, all deaths, which was twenty two percent higher with febuxostat. As you know, the FDA put out a warning that they're studying this data with febuxostat and that more to follow.
This is some of that data that they were alluding to in that warning that we spoke about two months ago. This data follows the history of the febuxostat. As you know, in the drug development and when this was up for approval by the FDA, they initially gave them a complete response letter, I believe, or they delayed the decision and recalled for another study because in the early studies, patients that were on febuxostat did have more cardiovascular events than patients that were on allopurinol. So they made the company go back and do a very specific study called the CONFIRM study, which was a similar study as is this CARE study, but it showed the exact opposite of the original data. Showed actually there were higher rates of cardiovascular events in allopurinol than with febuxostat and that led to the approval of the drug and it's being marketed since 2009.
Again, I think a lot of people feel fobuxostat is a very useful drug. Some of the caveats in this study are that there was a high dropout rate, about sixty percent of patients dropped out before the end of the study, that the flare rates between the two drugs were about the same, and that febuxostat patients were more likely to achieve a lower urate less than five point zero compared to allopurinol patients. Now, dose escalations were allowed, and I'm not sure I believe that forty milligrams of febuxostat is equal to three hundred of allopurinol in potency, but in both groups, about forty percent of patients increase their doses to achieve a target serum urate level. It remains to be seen what the long term success is of febuxostat. As you know, this was a Takeda drug and now I believe it's going off patent or it's been off patent.
It'll be interesting to see what the effects are of this kind of data is going to be in the long run. I'll leave you with a quote or a tweet that I posted this week. A goal without a plan is just a wish. This comes from Antoine de Saint Exupery, and I heard this at a presentation in Prague last week by Christine Bundy, a psychologist who was giving a great talk on motivational interviewing. She reminded us that goals are specific, measurable, attainable, realistic and timely.
Again, a goal without a plan is just a wish. That's it for RheumNow this week. Go to the website to find these links and more information on whatever hit your fancy in this report. We'll be back next week with more reports from roomnow.com.
I don't know about you, but during my training, induced lupus was sort of a big deal. There's a lot of talk about it, there were some cases of it. It's kind of exciting when you saw it, when you talked about it, when you learned about it. Haven't seen a good case of drug induced lupus in many, many years, but what we have heard a lot about in the last year are these immune related adverse events associated with checkpoint inhibitors, these new miracle magical drugs in cancer. Well, there's yet another report in the literature this week on a meta analysis of several of these drugs, novelimumab, pembrolizumab, pembrolizumab, and atezolizumab.
It's even hard for rheumatologists to talk about new mAbs. But anyway, when they reviewed the existing literature that's out there, they showed what the predominance was as far as these immune related adverse events that have an autoimmune nature. At the top of the list actually is hypothyroidism with an eightfold increased risk. Next is pneumonitis with a fivefold increased risk, colitis with a threefold increased risk, hypophysitis, not something we usually talk about, but it's very common with this syndrome, and three point fourfold increased risk in rash, a double risk, in these people. Also leading the way as far as symptoms that are commonly seen in these patients are fatigue, diarrhea in twenty percent, and probably around twenty percent or more of our patients that, will present to us will present because of arthralgia or back pain associated with the checkpoint inhibitors.
It's a nice review, you can look at that to find out more information. Again, we have a lot on the website about this topic. From science this week is a very interesting discussion on the Pathobion Enterococcus gallinarum. What is a pathobiont? A pathobiont, no, it's not a faculty member that you're working with.
It is a normal microbe that lives in symbiosis, but under certain circumstances can become pathologic. In this case, the, gut microbe Enterococcus gallinarum in certain situations just lives in the gut, but it has the ability to become invasive and in certain, or in certain genetic backgrounds may lead to autoimmunity. In this particular study, they actually showed that the enterococcus does lead and they use a mouse model for this. They looked at and they specifically use a mouse model that has a genetic predisposition to lupus and autoimmunity. When They were, colonnaded with enterococcus gallinearum, they actually had tissue invasion and that led to, pathogenic autoantibodies and Treg cells and really the onset of what was an autoimmune syndrome, not quite lupus, the way they played it out.
The same bug has been associated with autoimmune hepatitis in animal models. More interestingly, in this particular report, they showed that if you treat the animals that have been infected with vancomycin, you can prevent mortality and autoimmunity by suppressing the growth of E. Galanarum and eliminating those pathogenic autoantibodies and T cells. So it's a nice model whereby the microbiome becomes disorder disrupted in someone who are in a species that may have a risk for lupus like disease. This follows well on the coattails of the report that was done at ACR by Greg Silverman showing you some of the microbiome changes that may be associated with lupus and specifically with lupus nephritis.
You can find that on the website. There was a nice video by Greg, on our website that you can look at. A new study about GPA shows in Italy, they studied a cohort of 89 patients and specifically looked at it was a much larger cohort of GPA patients, but specifically they looked at eighty nine patients who had ENT involvement. They found ENT involvement in seventy two percent of their patients. Such patients who had ENT, GPA tended to be younger, They tended to have less renal disease.
Important because you don't want renal disease with GPA. The most dominant, of the ENT symptoms were sino nasal symptoms seen in almost sixty percent of patients and of the otic manifestations, thirty five percent either had otitis media or otomastoiditis. Overall, it turns out that ENT involvement predicted better outcomes with GPA, milder disease, a lower overall risk of renal disease, and overall better mortality. Something to be hopeful for when managing and seeing patients with GPA. An interesting study comes from Glasgow.
This is a study that was actually just reported this past week at the American Academy of Orthopedic Surgery meeting. This is a study that comes from the Golden Jubilee National Hospital in Glasgow where they studied the impact of how patients following their lower limb arthroplasty, hip or knee arthroplasty, how they traveled when they came for their follow-up visits to the National Hospital. They looked at patients who traveled by land and I assume that means trains and cars and whatnot, and versus those who traveled by plane. Since it was Glasgow, the trips weren't that long. The average time was only about seventy two minutes in the air and then such patients had on average six such flights.
But when they looked at the overall numbers, and again, all these people post operatively were, being, prophylaxed with anticoagulants of some sort. Despite them all being treated the same, the introduction of air travel, increased the odds of developing a venous thromboembolic event. So they looked at both PEs and DVTs, and the overall rate for those that were traveling by land was zero point five eight percent. The rate for those who traveled by air was one point six five percent, almost a threefold increase in the risk of VTEs, in patients who had lower limb arthroplasties, followed in Glasgow. This is one of the first studies that actually showed us.
The question is, what are you going to do about it? The website I wrote, I, had bilateral knee replacements, I usually wear compression stockings when I'm going be on a flight that's any more than an hour. Now the utility of that is really not known, but I think that the idea of instructing your patients to maybe have some protective measures, there are a lot of things you can do, getting up and walking around, exercises, maybe even using anticoagulants for short term use, these should be considered until really good data comes along. Because one of the hazardous, most hazardous outcomes in patients with knee or hip replacement is the complication of a venous thromboembolic event. A nice study comes from the BSRBR, the British Biologics Registry, almost 20,000 patients follow for over one hundred and six thousand patient years, meaning these patients were roughly followed for more than five years of follow-up.
And they looked at the incidence of opportunistic infections, in this cohort. They found and it specifically excluded patients with TB. And what they did find was that, overall, their rate of opportunistic infections was a hundred and thirty four per hundred thousand or to put it in a number you might understand better is one point three per one thousand patient years. Again, that's a number I keep bringing up in other reports that these very rare events that people are very, very concerned about still have about a one in one thousand risks. That is the risk of an opportunistic infection in RA patients going on biologics.
Interestingly, they showed that excluding TB, there's no real difference in the rate of opportunistic infections when you look at the different biologic classes, TNF inhibitors, IL-six inhibitors, etc. Across the board, they're really about the same. The only differences were a few, that pneumocystis, urovecai infections were higher with rituximab compared to TNF inhibitors, and that rituximab patients actually had a lower rate of TB compared to the TNF inhibitors. And maybe the most dramatic is the dramatic fall in TB events. In 2002, the rate of TB events was seven eighty three per one hundred thousand and it dropped to thirty eight by twenty fifteen per one hundred thousand.
Now, the population rate in United States and The UK is about four to five per one hundred thousand for just TB. So these rates are still elevated even in 2015 at thirty eight, but it's certainly down dramatically compared to that in 2002. Speaks a lot for your current practices of screening, and making sure patients don't have TB prior to the initiation of such therapy. There's an interesting report that finally appeared in the literature that was covered in great depth at the ACR meeting and really raised the number of eyebrows and that is the finding of bone marrow edema in elite athletes. When you're looking at the SI joints and specifically these investigators looked at 20 recreational runners and 22 professional ice hockey players, and they made them exercise through a vigorous routine and they had, before and after, MRIs.
And specifically, they were looking for evidence of sacroiliitis as measured by bone marrow edema, one of the criteria, by ASAS, the organization that's made criteria for the study of patients with spondylitis. Overall, these elite athletes, these active athletes found a rate of thirty to forty one percent who had new bone marrow lesions, bone marrow edema following their exercise, suggesting that this may not be as specific a finding, and that its, utility may be questioned. What they didn't find in these people were erosive changes and that may be the distinguishing feature between patients who have axial spondyloarthritis and athletes or people who are involved in vigorous exercise. Plaquenil, we know is vitamin P for all our patients with lupus. The study comes from, the Alzheimer's Rheumatic Disease and the lupus, cohort followed, by Michelle Petrie and others, very large cohort.
The number was something like thirteen forty nine patients followed at the Hopkins Lupus Clinic longitudinally. What they looked at were the rates of flares in lupus patients prior to pregnancy, with pregnancy and in postpartum period. What they showed was that lupus patients have an increased rate of lupus flares during pregnancy. In fact, the fifty nine percent increase rate of flares. This is not surprising, but it's important number to know if you want to quote to your patients what the rate of flare, what the odds of flaring are.
Maybe more important from the study was that, being on Plaquenil dropped the rates of flare significantly. If you are not on Plaquenil, the hazard ratio of getting a flare during pregnancy was one point eight three, but if you were on Plaquenil, this dropped to one point two six. Again, further evidence that it's wise to continue hydroxychloroquine throughout the pregnancy in your lupus patients. Lastly, there's a study from the New England Journal that's published just yesterday, the CARE study. This was published both in several journals and comes out from the cardiology national meeting that's going on.
This is a study of six thousand one hundred ninety gout patients who have a history of cardiovascular disease and therefore at high risk for cardiovascular events. They're specifically looking at the development of a cardiovascular endpoint in patients who are either taking febuxostat forty milligrams a day or allopurinol three hundred milligrams a day, and those patients were allowed to adjust the dose of their urate lowering therapy upwards to achieve a target serum urate less than six. The purpose of the study was to get to the number of six 20 four adjudicated cardiovascular events. The primary endpoint was a combination of cardiovascular death, nonfatal MI, nonfatal stroke, unstable angina with urgent revascularization. Turns out that the primary endpoint was not different in these patients who received one drug or the other.
They were followed for a median of thirty two months and as long as eighty four months. A lot of the patients were followed for five or six years. After thirty two months, start to see a difference between the fabuxtat group and the allopurinol group that the lines would start to diverge as far as developing some of these events. It turns out that the significant difference was found in cardiovascular death, which was thirty four percent higher in the febuxostat group, and all cause mortality, all deaths, which was twenty two percent higher with febuxostat. As you know, the FDA put out a warning that they're studying this data with febuxostat and that more to follow.
This is some of that data that they were alluding to in that warning that we spoke about two months ago. This data follows the history of the febuxostat. As you know, in the drug development and when this was up for approval by the FDA, they initially gave them a complete response letter, I believe, or they delayed the decision and recalled for another study because in the early studies, patients that were on febuxostat did have more cardiovascular events than patients that were on allopurinol. So they made the company go back and do a very specific study called the CONFIRM study, which was a similar study as is this CARE study, but it showed the exact opposite of the original data. Showed actually there were higher rates of cardiovascular events in allopurinol than with febuxostat and that led to the approval of the drug and it's being marketed since 2009.
Again, I think a lot of people feel fobuxostat is a very useful drug. Some of the caveats in this study are that there was a high dropout rate, about sixty percent of patients dropped out before the end of the study, that the flare rates between the two drugs were about the same, and that febuxostat patients were more likely to achieve a lower urate less than five point zero compared to allopurinol patients. Now, dose escalations were allowed, and I'm not sure I believe that forty milligrams of febuxostat is equal to three hundred of allopurinol in potency, but in both groups, about forty percent of patients increase their doses to achieve a target serum urate level. It remains to be seen what the long term success is of febuxostat. As you know, this was a Takeda drug and now I believe it's going off patent or it's been off patent.
It'll be interesting to see what the effects are of this kind of data is going to be in the long run. I'll leave you with a quote or a tweet that I posted this week. A goal without a plan is just a wish. This comes from Antoine de Saint Exupery, and I heard this at a presentation in Prague last week by Christine Bundy, a psychologist who was giving a great talk on motivational interviewing. She reminded us that goals are specific, measurable, attainable, realistic and timely.
Again, a goal without a plan is just a wish. That's it for RheumNow this week. Go to the website to find these links and more information on whatever hit your fancy in this report. We'll be back next week with more reports from roomnow.com.
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