RheumNow Podcast Loretta Lynn Arthritis (3.29.19) Save
RheumNow Podcast Loretta Lynn Arthritis (3.29.19) by Dr. Cush
Transcription
It's the 03/29/2019. This is the RheumNow podcast. I'm doctor Jack Cush, executive editor of rheumnow.com. This week, why Loretta Lynn should have been a rheumatologist. Second, you don't know Jack.
And another about why lupus drugs won't work in vasculitis. Our first report comes from partners in Boston. Jeff Sparks and colleagues looked at three hundred and forty patients who were CCP positive, referred to their medical center, underwent testing, and they followed those who were CCP positive forward, basically about three years for a total of one thousand forty five patient years and showed that over time, twenty one point five percent of them developed rheumatoid arthritis. Factors more likely to be associated with the development of rheumatoid arthritis were largely higher titers. When they compared higher titers to lower titers, there was actually almost a five fold increased risk of developing rheumatoid arthritis, meaning a hazard ratio of four point eight three.
Higher levels of CCP, the rate went from twenty one percent up to forty six percent. So it's not that a preclinical RA, a first degree relative has seropositivity, we know it is the strength of titer and being double positive that augments the risk of developing rheumatoid arthritis in those who are worried about developing rheumatoid arthritis. An interesting study came out this week, I wrote about it today on abatacep and first time users of abatacep. Encouraging data comes from, Sion Kim and colleagues where they did a match cohort analysis of claims data patients. I think some Medicare patients were thrown in there.
They looked at 11,000 matched patients who had either started abatacep or started a TNF inhibitor and follow them until the event of interest. Here the event of interest was a hospitalizable infection, essentially a diagnosis of a serious infectious event. Turns out that when you looked at the patients, they were less with abatacep thirty seven versus forty seven with a TNF inhibitor with a overall hazard ratio of 0.78 with confidence intervals below one, suggesting that this was significant, suggesting there was a twenty two percent reduction in the risk of serious infections. Turns out the risk was really carried by, the comparison of abatacept to infliximab. When you separated out etanercept patients and the adalimumab treated patients, there was no significant difference in, hospitalizable infections.
But with infliximab, yes, there was. Most of these hospitalisable infections, the most significant numbers were really for pulmonary infections and not other like skin, joint, GI, etc. So, it sort of is good news. It sort of goes in line with some of the other data that says apotaxis may in fact have lower rates of serious infectious events, and that may be important in how you use this drug in patients who need biologics. There's another report that we wrote about showing that abatacept compared to other biologic DMARDs was associated with a slightly higher risk of cancer, and that was a slightly higher overall cancer risk.
I think it was the hazard ratio, the adjusted hazard ratio was zero was 1.12. But it was only significant for non melanoma skin cancer, other skin cancers like melanoma, and not other types of cancer including solid tumors. So it's hard to say what that means. It's a small number. Patients the patient numbers were large.
It's a small difference in risk. I think it needs to be repeated before we start worrying about, abatacep risk of infection, of not infection, but, cancer. There was two tweets this week on doc a recent Doximity report on physician salaries and the gap between males and females. What I took away from that when I started looking through it, you can click on the link that we provide, it'll take you to Doximity and their report, and it shows you that rheumatologists are amongst the lowest paid of all the medical specialties. Although you're not the lowest, you're fourteenth from the bottom.
And while the numbers look good, I think it was like 250,000 or something like that. I'm just wondering when am I gonna see some of that money? But the other interesting thing about this report said that the, gap between physicians, male and female physicians with females earning substantially less has been narrowed over time. It's dropped I think by 15 nearly 15,000 from a previous gap of 105,000 to about a $90,000 gap between, again, males and females. They showed you what cities, had the worst gap, what had the best gap.
Turns out places like, Jacksonville and Milwaukee had the least gap and Birmingham had the least gap and actually places like Dallas had the worst gap. Interestingly amongst rheumatologists, there's not that much of a male female physician payment gap. There are other specialties, mainly the high pain specialties where where there's a big gap. You might want to look at that. How do JAK inhibitors work?
I don't know if you can easily answer that question. There's a lot of hand wringing and pointing out whether it's a JAK one, two or three or tick inhibitor and what it might do cytokine wise. Most of those cytokines they point to aren't the ones that we typically think of as being important in the pathogenesis of RA. And a nice paper came out about, an in vitro study comparing the, potential of tofacitinib and other selective JAK inhibitors, specifically a JAK1 inhibitor and a selective JAK3 inhibitor. And when those drugs were used in murine, bone marrow derived macrophages or human monocytes, and they studied the effects, they showed that TOFA being a 123, sort of a general inhibitor or pan inhibitor, and the JAK1, selective JAK1 inhibitors were associated with significant reductions in stat one phosphorylation and gamma interferon production.
And this was not seen in the JAK3 inhibitors. So what the bottom line on this was it's a highly detailed paper, but I think it suggests that, when the JAKs work, they work on macrophage function more so than any other cell type. And and I think that, it might be better to use more selective JAKs than than more general JAKs, but we'll see that as these become, more available in the future in 2019 or 2020. A new announcement from BI. BI has submitted an application to both the FDA and the EMA in Europe for the approval of, Nintedinib, which is their tyrosine kinase inhibitor of multiple growth factors including VEGF fiber fiberglass growth factor receptor, and also PDGF, the platelet derived growth factor.
The this drug called is already approved, by the FDA for use in idiopathic pulmonary fibrosis and non small cell lung cancer. Its commercial name is Ovev, o o f e v. Sounds like a cartoon character's name more than a drug. Who names these drugs? I don't know which is worse now, the drug of the trade name or even the generic name.
It's getting tough to name a drug these days. But they're looking for a new indication of, Nintedinib in systemic sclerosis associated ILD. You know, they're doing studies in autoimmune associated ILD and specifically in systemic sclerosis. They, believe they have the data and that's why they're going forward with a regulatory submission. Be nice to have that, you know, ILD and, is becoming a more significant problem.
There's growing numbers of this and it's not just an idiopathic disorder anymore. It's got a lot of clinical associations, autoimmune associations, and certainly we know it's a big problem with systemic sclerosis. We need drug or drug development in this area. So I heard at this last week's, RheumNow Live, a great lecture by, Carol Langford. We had a great session on vasculitis with Philip CEO, Carol Langford, and Paul Monack from the BI.
Really covered a lot of ground. Carol gave a great lecture on GPA management and she challenged the audience with a lot of questions. She presented the data about belimumab use in patients with GPA. And this is based on a recently published study that we posted one hundred and two patients with ANCA associated vasculitis who were induced with either Rituxan or Citoxin and then put on maintenance therapy with ease of azathioprine and placebo or azathioprine and belimumab. Turns out that the addition of belimumab did nothing to affect the flare rates or relapse rates.
Those were not significantly different, meaning it probably doesn't add much as far as maintenance therapy. Now, this may not have been the best study designed to show this, but it's a fairly decent study design, a large number of patients. Again, I don't think there's any evidence out there right now that we should be considering this drug only approved for lupus in other conditions like vasculitis. We posted a report about coal miners having a higher risk of any arthritis, almost a twofold risk, and specifically a risk of rheumatoid arthritis with a hazard ratio of three point six. Now, that's the whole Loretta Lynn analogy I mentioned earlier, you know, Kolmeiner's daughter.
That's how she got started. We do know that environmental exposures play some role in rheumatoid arthritis. We do know that smoking is the biggest factor, especially in HLA Doctor beta one allele positive patients. But other, things besides these, hydrocarbons that are found in smoke can be also, implicated by, toxin exposure, noxious stimuli that that are of which there are numerous. And now the coal miners seem to have a higher rate.
Now the mechanisms here, who knows? This is really just a population based observational study. But I think it is interesting that, you know, long ago we said that scleroderma had its roots in coal mine exposure, and that was mainly in patients in those regions where coal mines were operative. It's not to me surprising that it might also be implicated elsewhere. We posted a nice report about soluble program death protein one or PD-one as a soluble protein can be measured as a biomarker for vasculitis.
So a small study, fifty nine patients with ANCA associated vasculitis, they looked at a number of biomarkers including soluble PD-one and showed that it was actually correlated with BVAS, the Birmingham Vasculitis Activity Score, as a measure of vasculitis activity. The soluble PD one was associated or correlated with a hemoglobin and serum albumin levels, but not correlated with sed rate and CRP. So by comparison, don't think the correlation coefficients were as high with the soluble PD one inhibitor, but I like the idea that they're looking at other biomarkers as we struggle to find biomarkers, especially in ANCA associated vasculitis. So we'll just like to like to look at more research in on biomarkers like this. I posted something that was posted almost six months ago because it came up again in the news.
NHANES study says that there are now 9,200,000 people in The United States who have gout. That includes five point nine million men and three point three million women. By comparison and much more prevalent is over twenty million who actually have, nephrolithiasis. Now, the striking thing about this NHANES study published by Choi and colleagues was that the, use of urate lowering therapy was shockingly low. I'm sorry, the prevalence of hyperuricemia was twenty percent.
The number of nephrolithiasis cases is probably around twenty million, but I don't think that number was in the tweet. But what was really shocking to me was that only one third of patients with gout are taking, urate lowering therapy. So again, these are numbers that again tell us that gout's a bigger problem than we think, and actually our treatment of it is probably not really sufficient. The big news probably of the week was the release of information yesterday by the FDA that cerdulizumab, Cimzia, has been approved for non radiographic axial SpA. There's quite a story behind this.
As you know, both, cerdulizumab and adalimumab went in front of the FDA about four or five years ago to get a non radiographic axial SpA indication for studies they had done, except they couldn't convince the arthritis advisory panel that non radiographic axial SPA was a significant condition here in The United States and that, of course, it is an approved indication in the EU, and that we would need more studies to do that. AbbVie did not go forward in doing, other studies on this. Don't know if they're gonna go after that indication, but turns out that UCB did and based on a 03/2019 patient study where they looked at ASAS outcomes, there were significantly better outcomes when atalimumab, sorry, when cerdulizumab was given to patients with non radiographic axial SpA. Of course, the comparative group here were those who were taking placebo. So this is a nice advance.
That's it for this week on rheumnow. You can go to the website to click on these links to learn more information about these citations. Be sure to go to rheumnow.live and click on our link to register, and you can now watch the proceedings of the whole sixteen hour meeting for free at home, at your desktop, and at your leisure. Room now live, room now free. Check it out.
Goodbye.
And another about why lupus drugs won't work in vasculitis. Our first report comes from partners in Boston. Jeff Sparks and colleagues looked at three hundred and forty patients who were CCP positive, referred to their medical center, underwent testing, and they followed those who were CCP positive forward, basically about three years for a total of one thousand forty five patient years and showed that over time, twenty one point five percent of them developed rheumatoid arthritis. Factors more likely to be associated with the development of rheumatoid arthritis were largely higher titers. When they compared higher titers to lower titers, there was actually almost a five fold increased risk of developing rheumatoid arthritis, meaning a hazard ratio of four point eight three.
Higher levels of CCP, the rate went from twenty one percent up to forty six percent. So it's not that a preclinical RA, a first degree relative has seropositivity, we know it is the strength of titer and being double positive that augments the risk of developing rheumatoid arthritis in those who are worried about developing rheumatoid arthritis. An interesting study came out this week, I wrote about it today on abatacep and first time users of abatacep. Encouraging data comes from, Sion Kim and colleagues where they did a match cohort analysis of claims data patients. I think some Medicare patients were thrown in there.
They looked at 11,000 matched patients who had either started abatacep or started a TNF inhibitor and follow them until the event of interest. Here the event of interest was a hospitalizable infection, essentially a diagnosis of a serious infectious event. Turns out that when you looked at the patients, they were less with abatacep thirty seven versus forty seven with a TNF inhibitor with a overall hazard ratio of 0.78 with confidence intervals below one, suggesting that this was significant, suggesting there was a twenty two percent reduction in the risk of serious infections. Turns out the risk was really carried by, the comparison of abatacept to infliximab. When you separated out etanercept patients and the adalimumab treated patients, there was no significant difference in, hospitalizable infections.
But with infliximab, yes, there was. Most of these hospitalisable infections, the most significant numbers were really for pulmonary infections and not other like skin, joint, GI, etc. So, it sort of is good news. It sort of goes in line with some of the other data that says apotaxis may in fact have lower rates of serious infectious events, and that may be important in how you use this drug in patients who need biologics. There's another report that we wrote about showing that abatacept compared to other biologic DMARDs was associated with a slightly higher risk of cancer, and that was a slightly higher overall cancer risk.
I think it was the hazard ratio, the adjusted hazard ratio was zero was 1.12. But it was only significant for non melanoma skin cancer, other skin cancers like melanoma, and not other types of cancer including solid tumors. So it's hard to say what that means. It's a small number. Patients the patient numbers were large.
It's a small difference in risk. I think it needs to be repeated before we start worrying about, abatacep risk of infection, of not infection, but, cancer. There was two tweets this week on doc a recent Doximity report on physician salaries and the gap between males and females. What I took away from that when I started looking through it, you can click on the link that we provide, it'll take you to Doximity and their report, and it shows you that rheumatologists are amongst the lowest paid of all the medical specialties. Although you're not the lowest, you're fourteenth from the bottom.
And while the numbers look good, I think it was like 250,000 or something like that. I'm just wondering when am I gonna see some of that money? But the other interesting thing about this report said that the, gap between physicians, male and female physicians with females earning substantially less has been narrowed over time. It's dropped I think by 15 nearly 15,000 from a previous gap of 105,000 to about a $90,000 gap between, again, males and females. They showed you what cities, had the worst gap, what had the best gap.
Turns out places like, Jacksonville and Milwaukee had the least gap and Birmingham had the least gap and actually places like Dallas had the worst gap. Interestingly amongst rheumatologists, there's not that much of a male female physician payment gap. There are other specialties, mainly the high pain specialties where where there's a big gap. You might want to look at that. How do JAK inhibitors work?
I don't know if you can easily answer that question. There's a lot of hand wringing and pointing out whether it's a JAK one, two or three or tick inhibitor and what it might do cytokine wise. Most of those cytokines they point to aren't the ones that we typically think of as being important in the pathogenesis of RA. And a nice paper came out about, an in vitro study comparing the, potential of tofacitinib and other selective JAK inhibitors, specifically a JAK1 inhibitor and a selective JAK3 inhibitor. And when those drugs were used in murine, bone marrow derived macrophages or human monocytes, and they studied the effects, they showed that TOFA being a 123, sort of a general inhibitor or pan inhibitor, and the JAK1, selective JAK1 inhibitors were associated with significant reductions in stat one phosphorylation and gamma interferon production.
And this was not seen in the JAK3 inhibitors. So what the bottom line on this was it's a highly detailed paper, but I think it suggests that, when the JAKs work, they work on macrophage function more so than any other cell type. And and I think that, it might be better to use more selective JAKs than than more general JAKs, but we'll see that as these become, more available in the future in 2019 or 2020. A new announcement from BI. BI has submitted an application to both the FDA and the EMA in Europe for the approval of, Nintedinib, which is their tyrosine kinase inhibitor of multiple growth factors including VEGF fiber fiberglass growth factor receptor, and also PDGF, the platelet derived growth factor.
The this drug called is already approved, by the FDA for use in idiopathic pulmonary fibrosis and non small cell lung cancer. Its commercial name is Ovev, o o f e v. Sounds like a cartoon character's name more than a drug. Who names these drugs? I don't know which is worse now, the drug of the trade name or even the generic name.
It's getting tough to name a drug these days. But they're looking for a new indication of, Nintedinib in systemic sclerosis associated ILD. You know, they're doing studies in autoimmune associated ILD and specifically in systemic sclerosis. They, believe they have the data and that's why they're going forward with a regulatory submission. Be nice to have that, you know, ILD and, is becoming a more significant problem.
There's growing numbers of this and it's not just an idiopathic disorder anymore. It's got a lot of clinical associations, autoimmune associations, and certainly we know it's a big problem with systemic sclerosis. We need drug or drug development in this area. So I heard at this last week's, RheumNow Live, a great lecture by, Carol Langford. We had a great session on vasculitis with Philip CEO, Carol Langford, and Paul Monack from the BI.
Really covered a lot of ground. Carol gave a great lecture on GPA management and she challenged the audience with a lot of questions. She presented the data about belimumab use in patients with GPA. And this is based on a recently published study that we posted one hundred and two patients with ANCA associated vasculitis who were induced with either Rituxan or Citoxin and then put on maintenance therapy with ease of azathioprine and placebo or azathioprine and belimumab. Turns out that the addition of belimumab did nothing to affect the flare rates or relapse rates.
Those were not significantly different, meaning it probably doesn't add much as far as maintenance therapy. Now, this may not have been the best study designed to show this, but it's a fairly decent study design, a large number of patients. Again, I don't think there's any evidence out there right now that we should be considering this drug only approved for lupus in other conditions like vasculitis. We posted a report about coal miners having a higher risk of any arthritis, almost a twofold risk, and specifically a risk of rheumatoid arthritis with a hazard ratio of three point six. Now, that's the whole Loretta Lynn analogy I mentioned earlier, you know, Kolmeiner's daughter.
That's how she got started. We do know that environmental exposures play some role in rheumatoid arthritis. We do know that smoking is the biggest factor, especially in HLA Doctor beta one allele positive patients. But other, things besides these, hydrocarbons that are found in smoke can be also, implicated by, toxin exposure, noxious stimuli that that are of which there are numerous. And now the coal miners seem to have a higher rate.
Now the mechanisms here, who knows? This is really just a population based observational study. But I think it is interesting that, you know, long ago we said that scleroderma had its roots in coal mine exposure, and that was mainly in patients in those regions where coal mines were operative. It's not to me surprising that it might also be implicated elsewhere. We posted a nice report about soluble program death protein one or PD-one as a soluble protein can be measured as a biomarker for vasculitis.
So a small study, fifty nine patients with ANCA associated vasculitis, they looked at a number of biomarkers including soluble PD-one and showed that it was actually correlated with BVAS, the Birmingham Vasculitis Activity Score, as a measure of vasculitis activity. The soluble PD one was associated or correlated with a hemoglobin and serum albumin levels, but not correlated with sed rate and CRP. So by comparison, don't think the correlation coefficients were as high with the soluble PD one inhibitor, but I like the idea that they're looking at other biomarkers as we struggle to find biomarkers, especially in ANCA associated vasculitis. So we'll just like to like to look at more research in on biomarkers like this. I posted something that was posted almost six months ago because it came up again in the news.
NHANES study says that there are now 9,200,000 people in The United States who have gout. That includes five point nine million men and three point three million women. By comparison and much more prevalent is over twenty million who actually have, nephrolithiasis. Now, the striking thing about this NHANES study published by Choi and colleagues was that the, use of urate lowering therapy was shockingly low. I'm sorry, the prevalence of hyperuricemia was twenty percent.
The number of nephrolithiasis cases is probably around twenty million, but I don't think that number was in the tweet. But what was really shocking to me was that only one third of patients with gout are taking, urate lowering therapy. So again, these are numbers that again tell us that gout's a bigger problem than we think, and actually our treatment of it is probably not really sufficient. The big news probably of the week was the release of information yesterday by the FDA that cerdulizumab, Cimzia, has been approved for non radiographic axial SpA. There's quite a story behind this.
As you know, both, cerdulizumab and adalimumab went in front of the FDA about four or five years ago to get a non radiographic axial SpA indication for studies they had done, except they couldn't convince the arthritis advisory panel that non radiographic axial SPA was a significant condition here in The United States and that, of course, it is an approved indication in the EU, and that we would need more studies to do that. AbbVie did not go forward in doing, other studies on this. Don't know if they're gonna go after that indication, but turns out that UCB did and based on a 03/2019 patient study where they looked at ASAS outcomes, there were significantly better outcomes when atalimumab, sorry, when cerdulizumab was given to patients with non radiographic axial SpA. Of course, the comparative group here were those who were taking placebo. So this is a nice advance.
That's it for this week on rheumnow. You can go to the website to click on these links to learn more information about these citations. Be sure to go to rheumnow.live and click on our link to register, and you can now watch the proceedings of the whole sixteen hour meeting for free at home, at your desktop, and at your leisure. Room now live, room now free. Check it out.
Goodbye.
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