The RheumNow Week In Review - 6 October 2017 Save
The RheumNow Week In Review - 6 October 2017 by Dr. Cush
Transcription
Hi, I'm Jack Cush, Executive Editor of roomnow.com. It's the 10/06/2017, and this is the RoomNow Weekend Review. This week on our report, we're going to talk about cancer rates. We're going to talk about what happens when autoimmune disease occurs in patients with autoimmune disease. We're going to talk about what the most or best selling drugs are in rheumatology for 2016.
I'll bet you can't guess the top five. At the top of the news, there's an interesting study that looks at the rate of non serious infections in RA patients. Non serious infections would be infections like the sniffles, bronchitis, the flu, pharyngitis, UTI. These things happen to all of us every day. It turns out that actually RA patients, especially RA patients over the age of 65, have an increased rate more so than the general population.
A very large study done in an Ontario database by Will Dixon was published a few years ago and it showed that the rate was forty seven point five NSIEs per 100 patient years, meaning that in a year that the average RA patient is going to have an infection at least half the time. This is very important, and although this is an old report, I included this week in the news because I wrote a blog this week about how to manage infections and biologic or DMARDs. And basically I said, I don't stop biologics or DMARDs in patients who have infections unless they have very high fevers, unless they're in the hospital. The evidence of this is overwhelming and you should look at it and look at the blog on this. But you need to know this background data from Will Dixon that again, these events are very, very common.
You also need to know that when these drugs are being developed, all these biologics we've used, all the ones that have the warnings that are on television, they all had non serious infection events. In fact, it was a number one side effect seen in all the trials, occurring anywhere from thirty five to fifty five percent of the time. And nowhere in those trials was there a mandate to stop the study drug or withdraw the patient. Patients powered through, continued their study drug, whether it be placebo or the actual biologic. No one got sick, no one died.
Catherine Dow and I did a meta analysis of these and showed that even NSI were not statistically increased in patients on biologic, although there was a trend. It's just like the same story you see with serious infectious events. So you can stop, but I'm making a pitch for not stopping because you're spreading the word that these drugs cause infection when in fact the evidence for that is really quite scant. So you can look at those two reports. Another report about clinically suspect arthralgia, a cohort of two forty one patients who've had arthralgias that have been persistent were studied with regard to their serologies.
And in this particular study, they showed that positive serologies did increase the risk of ultimately developing RA within the next two years. The hazard ratio associated with CCP was as high as 8.5. For rheumatoid, it was as high as five, and CAR P antibodies, anti carbamylated P antibodies, was as high as three point nine. If you were double positive for rheumatoid factor and CCP, the positive predictive value of that was sixty seven percent, meaning two thirds of such patients who have clinically suspect polyarthralgia and who were double positive, not surprisingly, two thirds of them will develop rheumatoid arthritis. Another sort of related report comes about the use of ultrasound.
In 2016 oh no, the use of ultrasound. Where is that study? It's on my paper here. I'm going to have to find it later. Let's go back to my list.
The frequency of secondary Sjogren's syndrome. You know, I once had the pleasure of driving Norman Talal, who was famous for his work and research in Sjogren's syndrome, a professor of medicine and rheumatology from UT San Antonio. He was visiting Dallas, I drove him from the airport to our grand rounds. And I was a fellow at the time, and he asked me, what's the number one autoimmune disease amongst all of our patients in the world? And dopey me said, I don't know.
I don't know what I said. Rheumatoid arthritis? And of course he, who is world famous for Sjogren's, told me it was Sjogren's syndrome. You know, of course he was including patients with secondary Sjogren's syndrome. So a nice bit of research has shown that the frequency of secondary Sjogren's is not uncommon amongst autoimmune diseases, especially in patients with RA where it is seen twenty percent of the time and in lupus where it's seen fourteen percent of the time.
The interesting thing about having secondary Sjogren's is it is a female dominant finding. It's fifteen to one females to males when it comes to secondary Sjogren's for both RA and for lupus. So an interesting study comes from the Corona group, where they actually looked at the association between infectious risk and disease activity. And they showed that in their patients who had low disease activity or remission, that there was no increased rate of SIEs in patients in their very large database followed longitudinally. They showed that it was the risk of SIEs was thirty percent higher when the infection rate rose and you went in to the moderate to high disease activity group using the DAS.
So basically, they showed what others have shown. It's inflammation that drives infection risk, not the drugs. One hundred and seven JIA patients were on biologics for three years, and this particular report showed a very high rate of serious and or opportunistic infections ranging from ten point six to nearly fifteen SIEs per 100 patient years. Now remember, we don't know a background rate in JIA, but I would expect to be much lower than adult RA. The adult RA background SIE rate is three to nine per 100 patient years.
And here in JIA on a biologic, it's really ten to fifteen, which I think is a substantial increase. In their cohort of one hundred and seven patients, twenty five percent or thirty five patients did have SI, a serious infection or an opportunistic infection. An interesting retrospective review of tofacitinib and its experience with lymphoma. Those of you may not remember, a few years ago when tofacitinib was being first approved, one of the early concerns was there may be a cancer risk and including lymphoma risk. You know, this is what's gone around with the TNF inhibitors and RA, and it's ultimately been shown that there doesn't seem to be a cancer risk associated with tofacitinib.
And this is a review of 19 randomized controlled trials in 6,000, almost six thousand two hundred patients who received tofacitinib for over nineteen thousand patient years. They found nineteen patients who developed lymphoma, and a variety that you would see really with RA, a few being EBV, most of them being B cell non Hodgkin's lymphoma. The SIR on this is 2.62, relatively low, equal to that seen, actually less than that seen with many of the TNF inhibitors, and an overall rate of about one per one thousand patient years. A thousand patients following a year, one on tofacitinib is going develop a lymphoma. That kind of falls into what I've always been saying about the really bad, ugly risks.
There are one in one thousand risks. What is the top selling biologic and anti rheumatic drug in 2016? Drumroll please. Humira still at the top of the list at 13,600,000,000. Number two, Enbrel second in the list at 7,400,000,000.
Number three, Remicade still holding strong despite the surge or almost surge of biosimilars at 5,300,000,000. What's four and five on your list? Follow-up for Lyrica, 4,400,000,000. And number five, Rituximab, three point nine billion. Now that's not quite fair because most of that Rituximab use probably is in non Hodgkin's lymphoma CD20 positive B cell lymphomas.
So those are the top five drugs in 2016. If you look at patients, here's the report I was looking for before, those who have idiopathic arthralgias and you use ultrasound to detect synovitis, there is a predictive value to using ultrasound. I don't use ultrasound, my partners do, we know that many of the young rheumatologists and fellows are using this and finding a place for it in practice remains to be seen. But here's a good example, idiopathic arthralgia. If you do not find synovitis using standardized methodology, maybe an ultrasound seven score, a negative ultrasound test or a negative ultrasound screen has a negative predictive value of eighty nine percent for the future development of inflammatory arthritis.
I think that's powerful. An interesting review of what happens in patients with rheumatoid arthritis and who are included in clinical trials if they have comorbidities, specifically comorbidities of depression and or fibromyalgia or patients who are on SSRIs. Such patients, FM, depression, or SSRI patients who have RA in clinical trials have a ten percent less ACR 20 response rate and about half the LDAS, low disease activity responses, and they're more likely to have drug withdrawals and adverse events. Not a good idea. If you're doing clinical trials, designing clinical trials, you've got to exclude patients with fibromyalgia, depression and those on SSRIs.
You're tainting the data, you're confusing and cluttering up and increasing the noise. Again, in clinical trials, especially clinical trials, you need to as homogeneous and as pure as possible. That may not equate very well to real life, but you're going get the answers you need by cleaning up your inclusion exclusion criteria. What happens as far as psoriasis and psoriatic arthritis, what's the relationship? A nice study looked at that.
First off, they showed that seven to fifteen percent of patients psoriatic arthritis precedes psoriasis. That's kind of, and some of those will be psoriatic arthritis, sinnae psoriasis, meaning they'll never develop psoriasis, it's more likely in young people and kids. The remainder who actually have arthritis after psoriasis, the median time frame, and this is looking at two different cohorts, that's why I'm giving you two different numbers, the median time to develop psoriatic arthritis after the onset psoriasis is seven to eight years. Another analysis basically shows that about somewhere between sixty and seventy five percent of patients will get their psoriatic arthritis within ten to fifteen years after the onset of psoriasis. A nice report looked at the influence of, inflammatory bowel disease on the development of subsequent autoimmune and inflammatory disorders.
In this cohort, they scanned for up to 20 autoimmune disorders. They did show that IBD patients compared to controls were at higher risk for autoimmune inflammatory disorders, and it was different between those who had a background of ulcerative colitis or Crohn's disease. Ulcerative colitis patients were more likely to have autoimmune hepatitis, primary biliary cholangitis, Graves' disease, PMR, to mention a few. Crohn's patients were actually more likely to have psoriatic arthritis and episcoritis. Interestingly, if you look at subsets of the UC UC in Crohn's patients and include women in there, women with Crohn's are more likely to have RA and UC patients who are women are more likely to have RA as well.
So being female tends to to color the onset of rheumatoid and inflammatory arthritis in both those cohorts. An interesting look at a fairly large Canadian cohort of autoimmune patients with regard to biologic use. Now, of course, most autoimmune patients are younger, more likely to be female, and they're going to have active disease. Continuing drugs is a real big issue. This was an observational study and it showed that over a twelve year period from 2000 to 2012, the use of biologics went from zero to nearly six percent.
And that during that time, and it was mostly TNF inhibitors that were making up that group, amongst over seven thousand patients with autoimmune disease, they did find that there was one hundred and thirty one who met the criteria of having an autoimmune disease, who got pregnant and who went on a biologic. So that's one hundred and thirty one women, half of them had RA, the other half had inflammatory bowel disease. And what they did show was that in the first trimester, a third of them would stop their biologic, and the second trimester, a second third would stop their biologic and the remaining third continued throughout the pregnancy. They also showed that amongst all the patients, the patients included IBD and RA, but also MSAS, psoriasis, and I think JIA, actually MS patients. They also showed that RA patients were three times more likely to stop therapy compared to patients with Crohn's.
We know Crohn's patients almost always continue their biopurines and their biologics throughout with really no hazard, but the practice of stopping an RA, least that's what's observed, it's not always necessary that needs to happen, especially if the patient has active disease. They came away saying we need more research on how to manage patients with these autoimmune diseases if they're on a biologic. This is going be one of the charges of the ACR Pregnancy Guidelines Committee, which has just established and just started work just this last August. So we'll look forward to their work and guidance and hopefully more research in this area. And lastly, we'll talk about alcohol related deaths and psoriasis.
Patients with psoriasis have a higher degree of alcohol related deaths. It's pretty uncommon. The actual rate is about five per ten thousand patient years, but that's almost double that seen in those, in the general population who does not have psoriasis, with an overall, odds ratio of an alcohol related death being, I think it was almost, one point five eight or almost sixty percent higher, compared to the general population. The causes of alcohol related deaths were primarily alcohol related liver disease, and sixty five percent, twenty nine percent with either fibrosis or cirrhosis and about nine percent with mental or behavioral disorders. Alcohol related deaths are not uncommon in spondyloarthropathies and ankylosing spondylitis as well.
And it's part of the spectrum of comorbidities that's associated with these disorders. So a lot can be learned from this, important I guess is to counsel your patients about the use of alcohol and that it can be particularly deadly in patients with psoriasis who are much greater risk to develop fibrotic and cirrhotic liver disease with methotrexate, but also certainly with alcohol. That's it for this week in RheumNow. Go to the website, you can find these citations and more reading. Tune in next week for more good news.
For those of you in the New England area, you can go to arthros.org and sign up for the Downeaster meeting which occurs on Saturday, October 14. Take care and goodbye.
I'll bet you can't guess the top five. At the top of the news, there's an interesting study that looks at the rate of non serious infections in RA patients. Non serious infections would be infections like the sniffles, bronchitis, the flu, pharyngitis, UTI. These things happen to all of us every day. It turns out that actually RA patients, especially RA patients over the age of 65, have an increased rate more so than the general population.
A very large study done in an Ontario database by Will Dixon was published a few years ago and it showed that the rate was forty seven point five NSIEs per 100 patient years, meaning that in a year that the average RA patient is going to have an infection at least half the time. This is very important, and although this is an old report, I included this week in the news because I wrote a blog this week about how to manage infections and biologic or DMARDs. And basically I said, I don't stop biologics or DMARDs in patients who have infections unless they have very high fevers, unless they're in the hospital. The evidence of this is overwhelming and you should look at it and look at the blog on this. But you need to know this background data from Will Dixon that again, these events are very, very common.
You also need to know that when these drugs are being developed, all these biologics we've used, all the ones that have the warnings that are on television, they all had non serious infection events. In fact, it was a number one side effect seen in all the trials, occurring anywhere from thirty five to fifty five percent of the time. And nowhere in those trials was there a mandate to stop the study drug or withdraw the patient. Patients powered through, continued their study drug, whether it be placebo or the actual biologic. No one got sick, no one died.
Catherine Dow and I did a meta analysis of these and showed that even NSI were not statistically increased in patients on biologic, although there was a trend. It's just like the same story you see with serious infectious events. So you can stop, but I'm making a pitch for not stopping because you're spreading the word that these drugs cause infection when in fact the evidence for that is really quite scant. So you can look at those two reports. Another report about clinically suspect arthralgia, a cohort of two forty one patients who've had arthralgias that have been persistent were studied with regard to their serologies.
And in this particular study, they showed that positive serologies did increase the risk of ultimately developing RA within the next two years. The hazard ratio associated with CCP was as high as 8.5. For rheumatoid, it was as high as five, and CAR P antibodies, anti carbamylated P antibodies, was as high as three point nine. If you were double positive for rheumatoid factor and CCP, the positive predictive value of that was sixty seven percent, meaning two thirds of such patients who have clinically suspect polyarthralgia and who were double positive, not surprisingly, two thirds of them will develop rheumatoid arthritis. Another sort of related report comes about the use of ultrasound.
In 2016 oh no, the use of ultrasound. Where is that study? It's on my paper here. I'm going to have to find it later. Let's go back to my list.
The frequency of secondary Sjogren's syndrome. You know, I once had the pleasure of driving Norman Talal, who was famous for his work and research in Sjogren's syndrome, a professor of medicine and rheumatology from UT San Antonio. He was visiting Dallas, I drove him from the airport to our grand rounds. And I was a fellow at the time, and he asked me, what's the number one autoimmune disease amongst all of our patients in the world? And dopey me said, I don't know.
I don't know what I said. Rheumatoid arthritis? And of course he, who is world famous for Sjogren's, told me it was Sjogren's syndrome. You know, of course he was including patients with secondary Sjogren's syndrome. So a nice bit of research has shown that the frequency of secondary Sjogren's is not uncommon amongst autoimmune diseases, especially in patients with RA where it is seen twenty percent of the time and in lupus where it's seen fourteen percent of the time.
The interesting thing about having secondary Sjogren's is it is a female dominant finding. It's fifteen to one females to males when it comes to secondary Sjogren's for both RA and for lupus. So an interesting study comes from the Corona group, where they actually looked at the association between infectious risk and disease activity. And they showed that in their patients who had low disease activity or remission, that there was no increased rate of SIEs in patients in their very large database followed longitudinally. They showed that it was the risk of SIEs was thirty percent higher when the infection rate rose and you went in to the moderate to high disease activity group using the DAS.
So basically, they showed what others have shown. It's inflammation that drives infection risk, not the drugs. One hundred and seven JIA patients were on biologics for three years, and this particular report showed a very high rate of serious and or opportunistic infections ranging from ten point six to nearly fifteen SIEs per 100 patient years. Now remember, we don't know a background rate in JIA, but I would expect to be much lower than adult RA. The adult RA background SIE rate is three to nine per 100 patient years.
And here in JIA on a biologic, it's really ten to fifteen, which I think is a substantial increase. In their cohort of one hundred and seven patients, twenty five percent or thirty five patients did have SI, a serious infection or an opportunistic infection. An interesting retrospective review of tofacitinib and its experience with lymphoma. Those of you may not remember, a few years ago when tofacitinib was being first approved, one of the early concerns was there may be a cancer risk and including lymphoma risk. You know, this is what's gone around with the TNF inhibitors and RA, and it's ultimately been shown that there doesn't seem to be a cancer risk associated with tofacitinib.
And this is a review of 19 randomized controlled trials in 6,000, almost six thousand two hundred patients who received tofacitinib for over nineteen thousand patient years. They found nineteen patients who developed lymphoma, and a variety that you would see really with RA, a few being EBV, most of them being B cell non Hodgkin's lymphoma. The SIR on this is 2.62, relatively low, equal to that seen, actually less than that seen with many of the TNF inhibitors, and an overall rate of about one per one thousand patient years. A thousand patients following a year, one on tofacitinib is going develop a lymphoma. That kind of falls into what I've always been saying about the really bad, ugly risks.
There are one in one thousand risks. What is the top selling biologic and anti rheumatic drug in 2016? Drumroll please. Humira still at the top of the list at 13,600,000,000. Number two, Enbrel second in the list at 7,400,000,000.
Number three, Remicade still holding strong despite the surge or almost surge of biosimilars at 5,300,000,000. What's four and five on your list? Follow-up for Lyrica, 4,400,000,000. And number five, Rituximab, three point nine billion. Now that's not quite fair because most of that Rituximab use probably is in non Hodgkin's lymphoma CD20 positive B cell lymphomas.
So those are the top five drugs in 2016. If you look at patients, here's the report I was looking for before, those who have idiopathic arthralgias and you use ultrasound to detect synovitis, there is a predictive value to using ultrasound. I don't use ultrasound, my partners do, we know that many of the young rheumatologists and fellows are using this and finding a place for it in practice remains to be seen. But here's a good example, idiopathic arthralgia. If you do not find synovitis using standardized methodology, maybe an ultrasound seven score, a negative ultrasound test or a negative ultrasound screen has a negative predictive value of eighty nine percent for the future development of inflammatory arthritis.
I think that's powerful. An interesting review of what happens in patients with rheumatoid arthritis and who are included in clinical trials if they have comorbidities, specifically comorbidities of depression and or fibromyalgia or patients who are on SSRIs. Such patients, FM, depression, or SSRI patients who have RA in clinical trials have a ten percent less ACR 20 response rate and about half the LDAS, low disease activity responses, and they're more likely to have drug withdrawals and adverse events. Not a good idea. If you're doing clinical trials, designing clinical trials, you've got to exclude patients with fibromyalgia, depression and those on SSRIs.
You're tainting the data, you're confusing and cluttering up and increasing the noise. Again, in clinical trials, especially clinical trials, you need to as homogeneous and as pure as possible. That may not equate very well to real life, but you're going get the answers you need by cleaning up your inclusion exclusion criteria. What happens as far as psoriasis and psoriatic arthritis, what's the relationship? A nice study looked at that.
First off, they showed that seven to fifteen percent of patients psoriatic arthritis precedes psoriasis. That's kind of, and some of those will be psoriatic arthritis, sinnae psoriasis, meaning they'll never develop psoriasis, it's more likely in young people and kids. The remainder who actually have arthritis after psoriasis, the median time frame, and this is looking at two different cohorts, that's why I'm giving you two different numbers, the median time to develop psoriatic arthritis after the onset psoriasis is seven to eight years. Another analysis basically shows that about somewhere between sixty and seventy five percent of patients will get their psoriatic arthritis within ten to fifteen years after the onset of psoriasis. A nice report looked at the influence of, inflammatory bowel disease on the development of subsequent autoimmune and inflammatory disorders.
In this cohort, they scanned for up to 20 autoimmune disorders. They did show that IBD patients compared to controls were at higher risk for autoimmune inflammatory disorders, and it was different between those who had a background of ulcerative colitis or Crohn's disease. Ulcerative colitis patients were more likely to have autoimmune hepatitis, primary biliary cholangitis, Graves' disease, PMR, to mention a few. Crohn's patients were actually more likely to have psoriatic arthritis and episcoritis. Interestingly, if you look at subsets of the UC UC in Crohn's patients and include women in there, women with Crohn's are more likely to have RA and UC patients who are women are more likely to have RA as well.
So being female tends to to color the onset of rheumatoid and inflammatory arthritis in both those cohorts. An interesting look at a fairly large Canadian cohort of autoimmune patients with regard to biologic use. Now, of course, most autoimmune patients are younger, more likely to be female, and they're going to have active disease. Continuing drugs is a real big issue. This was an observational study and it showed that over a twelve year period from 2000 to 2012, the use of biologics went from zero to nearly six percent.
And that during that time, and it was mostly TNF inhibitors that were making up that group, amongst over seven thousand patients with autoimmune disease, they did find that there was one hundred and thirty one who met the criteria of having an autoimmune disease, who got pregnant and who went on a biologic. So that's one hundred and thirty one women, half of them had RA, the other half had inflammatory bowel disease. And what they did show was that in the first trimester, a third of them would stop their biologic, and the second trimester, a second third would stop their biologic and the remaining third continued throughout the pregnancy. They also showed that amongst all the patients, the patients included IBD and RA, but also MSAS, psoriasis, and I think JIA, actually MS patients. They also showed that RA patients were three times more likely to stop therapy compared to patients with Crohn's.
We know Crohn's patients almost always continue their biopurines and their biologics throughout with really no hazard, but the practice of stopping an RA, least that's what's observed, it's not always necessary that needs to happen, especially if the patient has active disease. They came away saying we need more research on how to manage patients with these autoimmune diseases if they're on a biologic. This is going be one of the charges of the ACR Pregnancy Guidelines Committee, which has just established and just started work just this last August. So we'll look forward to their work and guidance and hopefully more research in this area. And lastly, we'll talk about alcohol related deaths and psoriasis.
Patients with psoriasis have a higher degree of alcohol related deaths. It's pretty uncommon. The actual rate is about five per ten thousand patient years, but that's almost double that seen in those, in the general population who does not have psoriasis, with an overall, odds ratio of an alcohol related death being, I think it was almost, one point five eight or almost sixty percent higher, compared to the general population. The causes of alcohol related deaths were primarily alcohol related liver disease, and sixty five percent, twenty nine percent with either fibrosis or cirrhosis and about nine percent with mental or behavioral disorders. Alcohol related deaths are not uncommon in spondyloarthropathies and ankylosing spondylitis as well.
And it's part of the spectrum of comorbidities that's associated with these disorders. So a lot can be learned from this, important I guess is to counsel your patients about the use of alcohol and that it can be particularly deadly in patients with psoriasis who are much greater risk to develop fibrotic and cirrhotic liver disease with methotrexate, but also certainly with alcohol. That's it for this week in RheumNow. Go to the website, you can find these citations and more reading. Tune in next week for more good news.
For those of you in the New England area, you can go to arthros.org and sign up for the Downeaster meeting which occurs on Saturday, October 14. Take care and goodbye.
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