Pollution And Autoimmunity (7.12.2024) Save
Pollution and Autoimmunity (7.12.2024)
Transcription
It's 07/12/2024, and this is the RheumNow podcast. Hi. I'm doctor Jack Cush, executive editor of rheumnow.com. This is our return from the holiday vacation, and we've got a lot of interesting articles that we put up this week. Some of these have got to be of interest to you.
I'm gonna start off with some negative studies. I don't know if you've seen the research, but there's always been this research about zolundronic acid, you know, Reclass being, having some efficacy or some utility in the treatment of osteoarthritis. Well, there was an IV, zolundronic acid study in two twenty two knee OA patients who had symptomatic knee OA but were not bone on bone stage four Kellgren Lawrence, joint space narrowing. And it showed after seven years of follow-up, those who had the zolundronic acid therapy, had more requirements for total knee replacements than those that got placebo. So the hazard ratio was a negative 4.5 fold higher odds or or just has a ratio of 4.2.
Anyway, that's what it says. Point is that you get that it didn't work. In fact, it failed quite quite miserably. Colchicine, also now a big drug in the cardiology field. I saw this study I thought you might wanna know about.
It's not really a rheumatology study, but it's called the CHANCE three study, a double blind randomized placebo controlled trial of 8,000 adults over the age of 40 who have either mild to moderate symptoms of a stroke or a TIA, and they have elevated high sensitivity CRPs greater than two milligrams per liter. And they showed that half the four thousand or so people got colchicine, zero point five BID for a few days, and then once a day for ninety days had no, protection against subsequent strokes in ninety days. So when you look at the two groups, the subsequent stroke rate was six point three percent versus six point five percent. No significant difference, a negative study. Speaking of negative studies, the ones that really have bothered me in recent years were those studies that look like they might work regarding vagal nerve stimulation as a preventative non pharmacologic intervention in rheumatoid arthritis that basically vagal nerve stimulation would decrease TNF levels.
It would be like using a TNF inhibitor. The original studies, uncontrolled by Mark Genovese looked really exciting, but then the subsequent studies didn't look so good. And then the auricular stimulation one the ones that were supposed to sort of simulate vagal nerve stimulation, those failed. So here's another one. It's a preliminary study.
It's called the RESET RA study, and these are preliminary results. So I don't have details, but they said their primary endpoint and this was an actual implanted vagal nerve stimulator. It's usually done intermittently, not continuously. They read out an ACR twenty response rate in RA patients who, had not responded to usual therapy like methotrexate, two hundred and forty two patients, 12 peak twelve week endpoint, and significant re results suggesting that that vagal nerve stimulation would be beneficial. But, again, we don't have the, results on this two stage multicenter randomized sham controlled double blind pivotal trial.
So you'll be looking for that. Maybe that'll get all get presented at ACR. It wasn't presented at EULAR. We don't report enough about fibromyalgia here, and I found this large registry analysis of eighteen hundred plus PSA patients from the the old corona registry now called CORE Evitas. And they found amongst these eighteen hundred and twenty three PSA patients that eleven percent met criteria for fibromyalgia.
Moreover, twenty point six or twenty one percent had evidence of widespread pain. Both of these significantly impair our ability to adequately assess these patients or to successfully treat them. Fibromyalgia in this subset or in that subset fibromyalgia subset of patients with PSA were more likely to be female, have depression and anxiety, have impaired function, higher BMIs, meaning obesity, comorbidities. It was correlated with CDAPSA scores, patient pain, and tender joint count. So, again, you must be aware that secondary fibromyalgia and core and and widespread pain can affect our patients with inflammatory arthritis.
Bimekizumab, a drug that's being developed for psoriasis, actually approved for psoriasis being developed for psoriatic arthritis and axial spondyloarthritis was studied in two large phase three trials, the Mobil one and Mobil two studies. And we've reported on this from last ACR, but maybe you missed it. Bimekizumab, the dual IL seventeen, a and f inhibitor was shown to, prevent the onset of uveitis in those two two studies. So these are AXPA patients given either, placebo or bimekizumab and showed it worked on AXPA endpoints, but the patients couldn't enter the trial if they had active uveitis. They might have had a past history, but few did.
As far as new episodes of uveitis, it was, like, point six percent in the bimekizumab group and four almost five percent in the placebo group, and this was highly significant. In the small subset who had a history of uveitis, again, they had a significantly lower rate of developing uveitis if they were on the bimekizumab IL seventeen dual inhibitor. 6.2 events per 100 patient years for bimekizumab versus seventy if you were on placebo. Looks like you can add that to your list of drugs that will prevent uveitis. I don't know if you've had this head scratcher that I've had about paradoxical drug reactions.
We've seen, you know, paradoxical reactions with TNF inhibitors causing psoriasis and causing IBD. Well, we have paradoxical psoriasis being reported with IL seventeen inhibitors. So this is a literature review. They identified thirty five patients. Almost all of them were SPA patients.
They either presented as far as their psoriasis either as palomopustular, pomoplantar, pustular psoriasis or plaque psoriasis. But again, the palomoplantar psoriasis is what you see with the TNF inhibitors causing psoriasis as well. Anyway, this occurred immediately after, of eleven weeks after they started IL seventeen inhibitor. One a third of them continued the IL seventeen inhibitor and got better. Two thirds, they had to stop the IL seventeen inhibitor and switch to an another drug effective, another biologic effective for psoriasis, and they got better.
So it's a little bit of a selective reporting. Everybody got better whether they got better by stopping or not. Again, the data on TNF inhibitor associated paradoxal psoriasis is about one in one thousand cases. Most of them being, again, that pommel plantar variant, which is very difficult to treat. And the treatment is you gotta stop the TNF inhibitor.
Here, will is it gonna be the same with IL seventeen? I don't know. We need more reports like this. Some of you have asked questions about, do you only do rheumatoid factor and CCP testing? Do you do IgA rheumatoid factor and IgG this and and these other smaller, selective analyses of, autoantibodies that may appear early before the onset of disease.
Anyway, this is an early arthritis clinics analysis. Actually, patients entering the T REACH trial, which was an early arthritis study, showed that IgA ACPA was present in twenty three percent of those patients, which was significantly less than I think it was seventy percent for the IgG ACPA, but it overlapped with IgG ACPA in ninety four percent of the cases. In this population, ninety percent of patients were IgM rheumatoid factor positive. The point being doing IgA antibodies didn't matter at all in the assessment of these early arthritis patients, had no predictive value. I take that as a teaching point.
I found another interesting study on difficult to treat RA patients. This is from Tom Taguchi's, group in Japan I believe. Five year results, a 150 difficult to treat RA patients. They saw and they don't give me the incidence of d two t RA. It's generally about ten percent, maybe a little as high as fifteen percent in some studies.
Anyway, in their study, of the hundred 50 patients they followed, forty five percent of them of the difficult RA definition resolved, meaning they ultimately responded, but fifty percent persisted and five percent died. The resolved difficult to treat RA patients were younger, had more treatment changes, more IL six use, suggesting that maybe you should be treating them with newer drugs, especially if they're younger. Now, again, is the IL six use gonna be selective here? It tends to be used secondarily or or as third line in Japan, so I don't know how it's gonna pan out with the rest of the world. We need to wait and see.
Mortality was pretty in in in this cohort of a 150 difficult to treat patients, and as I said, was five percent, was predicted by comorbidity steroid escalation. Okay? And there the odds ratios was a comorbidity is three point five holder five three point five fold higher risk with comorbidities that were high, like three or more. And steroid escalation had a thirty two fold higher risk of mortality. Not good.
Takayasu's arteritis, we're sort of wrapping up now. If you give them biologics, will it matter? Will it help? In this cohort analysis of seventy five patients with Takayasu, were treated with conventional DMARDs, methotrexate, leflunomide, that kind of thing, azathioprine. Thirty five were given biologics, and they showed that that overall, a reduced, thickness artery thickness was seen in seventy three percent of their patients.
Thirty one percent decreased their arterial wall thickness by more than twenty five percent. And in the end, it was either the use of a biologic or other immunosuppressants like azathioprine that were able to reduce arterial wall thickness when they compared the results to those who just got conventional DMARDs. Makes a case for using biologics, and most of biologics used here were TNF inhibitors. Lastly, there's a study about pollution and the risk of lupus. I got two studies on the risk of lupus.
And one is that the study from the UK Biobank almost a half million people. And they actually did collect data on exposure to nitrous oxide and other kinds of pollutants. They showed that in the three hundred ninety nine patients who had lupus, they found a eighteen to twenty seven percent increased risk of lupus when they were exposed to these environmental pollutants. And it was even higher in lupus patients who had a genetic risk. I don't know what that's gonna be.
They didn't actually detail that in their report. But there's you know, we reported, like, three months ago about, polycyclic aromatic hydrocarbons also increasing the risk of lupus in the general population. And there's another report on RheumNow from yesterday about the pathogenesis of lupus, and it talks, again, about, environmental pollutants being important in the generation of the chemokine CXCL 13, which draw along which drives T cells to dry to to make more follicular helper T cells that will drive B cell activity, again related to, pollution. The other report comes from the nurses health study. This is from Karen Costenbatter's group.
And in this study, they lupus wasn't all that common. Amongst the Nurses Health Study, 200,000 nurses in two different, iterations of the Nurses Health Study, they had like four point five million years of observation, but only two hundred and twelve cases of new lupus. Right? These women tend to be a little bit older, I think. But nonetheless, that when they looked at their diets, the and they looked at the top turtle who were taking ultra processed food, a western diet, you know, Big Mac's, french fries, donuts.
These had an adjusted hazard ratio of one point five six, meaning fifty six percent higher risk of developing new onset incident lupus compared to those in the lowest turtle. So this is also soft drinks, and sugar sweetened products. So the idea is that, you know, there's this picture of of autoimmune disease now that has the environment as a strong predictor of risk. And it may be that in with certain genotypes that the risk gets even higher. Now you produce the autoimmune state, which is the preclinical state, which may evolve with a few other triggers into clinically manifest disease.
I think this kind of research is really framing our thinking, or maybe not just maybe confirming the way our thinking has been framed in the last few several years about how you get autoimmune disease. And the last report is on the cost effectiveness of biosimilars versus leflinomide. This is a Korean database that looked at, I think it was 26,000 patients and using Markov modeling, which is what how you assess the cost efficacy of a drug and whatnot. And here they looked at the lifetime cost of RA and the quality adjusted life years. They compared getting starting with leflunomide to starting with the bios the infliximab biosimilar CTP one three.
That's like Inflector and Rinflexis or the adalimumab biosimilar, ABP five zero one. And the cost lifetime cost of the disease was a 154,000 with leflunomide, a 152,000 with biosimilar infliximab, a 150 45,000 with biosimilar adalimumab. And the quality adjusted life years are all exactly the same. The point being that after after methotrexate, should you play around with conventional DMARDs or now with the cost of biosimilars becoming reasonable, can we go right to biosimilars? This is gonna challenge maybe how we treat our patients in the future.
Again, the great promise of biosimilars is going to be much cheaper, making it more widely available, and more patients being more aggressively treated. But, you know, in The United States, we've been very slow on the uptake of biosimilars. I think this data is going to help us make up our mind. That's it for this week on the podcast. Make sure you go to the website to check out these citations and more.
We'll talk to you next week. Take good care of yourself.
I'm gonna start off with some negative studies. I don't know if you've seen the research, but there's always been this research about zolundronic acid, you know, Reclass being, having some efficacy or some utility in the treatment of osteoarthritis. Well, there was an IV, zolundronic acid study in two twenty two knee OA patients who had symptomatic knee OA but were not bone on bone stage four Kellgren Lawrence, joint space narrowing. And it showed after seven years of follow-up, those who had the zolundronic acid therapy, had more requirements for total knee replacements than those that got placebo. So the hazard ratio was a negative 4.5 fold higher odds or or just has a ratio of 4.2.
Anyway, that's what it says. Point is that you get that it didn't work. In fact, it failed quite quite miserably. Colchicine, also now a big drug in the cardiology field. I saw this study I thought you might wanna know about.
It's not really a rheumatology study, but it's called the CHANCE three study, a double blind randomized placebo controlled trial of 8,000 adults over the age of 40 who have either mild to moderate symptoms of a stroke or a TIA, and they have elevated high sensitivity CRPs greater than two milligrams per liter. And they showed that half the four thousand or so people got colchicine, zero point five BID for a few days, and then once a day for ninety days had no, protection against subsequent strokes in ninety days. So when you look at the two groups, the subsequent stroke rate was six point three percent versus six point five percent. No significant difference, a negative study. Speaking of negative studies, the ones that really have bothered me in recent years were those studies that look like they might work regarding vagal nerve stimulation as a preventative non pharmacologic intervention in rheumatoid arthritis that basically vagal nerve stimulation would decrease TNF levels.
It would be like using a TNF inhibitor. The original studies, uncontrolled by Mark Genovese looked really exciting, but then the subsequent studies didn't look so good. And then the auricular stimulation one the ones that were supposed to sort of simulate vagal nerve stimulation, those failed. So here's another one. It's a preliminary study.
It's called the RESET RA study, and these are preliminary results. So I don't have details, but they said their primary endpoint and this was an actual implanted vagal nerve stimulator. It's usually done intermittently, not continuously. They read out an ACR twenty response rate in RA patients who, had not responded to usual therapy like methotrexate, two hundred and forty two patients, 12 peak twelve week endpoint, and significant re results suggesting that that vagal nerve stimulation would be beneficial. But, again, we don't have the, results on this two stage multicenter randomized sham controlled double blind pivotal trial.
So you'll be looking for that. Maybe that'll get all get presented at ACR. It wasn't presented at EULAR. We don't report enough about fibromyalgia here, and I found this large registry analysis of eighteen hundred plus PSA patients from the the old corona registry now called CORE Evitas. And they found amongst these eighteen hundred and twenty three PSA patients that eleven percent met criteria for fibromyalgia.
Moreover, twenty point six or twenty one percent had evidence of widespread pain. Both of these significantly impair our ability to adequately assess these patients or to successfully treat them. Fibromyalgia in this subset or in that subset fibromyalgia subset of patients with PSA were more likely to be female, have depression and anxiety, have impaired function, higher BMIs, meaning obesity, comorbidities. It was correlated with CDAPSA scores, patient pain, and tender joint count. So, again, you must be aware that secondary fibromyalgia and core and and widespread pain can affect our patients with inflammatory arthritis.
Bimekizumab, a drug that's being developed for psoriasis, actually approved for psoriasis being developed for psoriatic arthritis and axial spondyloarthritis was studied in two large phase three trials, the Mobil one and Mobil two studies. And we've reported on this from last ACR, but maybe you missed it. Bimekizumab, the dual IL seventeen, a and f inhibitor was shown to, prevent the onset of uveitis in those two two studies. So these are AXPA patients given either, placebo or bimekizumab and showed it worked on AXPA endpoints, but the patients couldn't enter the trial if they had active uveitis. They might have had a past history, but few did.
As far as new episodes of uveitis, it was, like, point six percent in the bimekizumab group and four almost five percent in the placebo group, and this was highly significant. In the small subset who had a history of uveitis, again, they had a significantly lower rate of developing uveitis if they were on the bimekizumab IL seventeen dual inhibitor. 6.2 events per 100 patient years for bimekizumab versus seventy if you were on placebo. Looks like you can add that to your list of drugs that will prevent uveitis. I don't know if you've had this head scratcher that I've had about paradoxical drug reactions.
We've seen, you know, paradoxical reactions with TNF inhibitors causing psoriasis and causing IBD. Well, we have paradoxical psoriasis being reported with IL seventeen inhibitors. So this is a literature review. They identified thirty five patients. Almost all of them were SPA patients.
They either presented as far as their psoriasis either as palomopustular, pomoplantar, pustular psoriasis or plaque psoriasis. But again, the palomoplantar psoriasis is what you see with the TNF inhibitors causing psoriasis as well. Anyway, this occurred immediately after, of eleven weeks after they started IL seventeen inhibitor. One a third of them continued the IL seventeen inhibitor and got better. Two thirds, they had to stop the IL seventeen inhibitor and switch to an another drug effective, another biologic effective for psoriasis, and they got better.
So it's a little bit of a selective reporting. Everybody got better whether they got better by stopping or not. Again, the data on TNF inhibitor associated paradoxal psoriasis is about one in one thousand cases. Most of them being, again, that pommel plantar variant, which is very difficult to treat. And the treatment is you gotta stop the TNF inhibitor.
Here, will is it gonna be the same with IL seventeen? I don't know. We need more reports like this. Some of you have asked questions about, do you only do rheumatoid factor and CCP testing? Do you do IgA rheumatoid factor and IgG this and and these other smaller, selective analyses of, autoantibodies that may appear early before the onset of disease.
Anyway, this is an early arthritis clinics analysis. Actually, patients entering the T REACH trial, which was an early arthritis study, showed that IgA ACPA was present in twenty three percent of those patients, which was significantly less than I think it was seventy percent for the IgG ACPA, but it overlapped with IgG ACPA in ninety four percent of the cases. In this population, ninety percent of patients were IgM rheumatoid factor positive. The point being doing IgA antibodies didn't matter at all in the assessment of these early arthritis patients, had no predictive value. I take that as a teaching point.
I found another interesting study on difficult to treat RA patients. This is from Tom Taguchi's, group in Japan I believe. Five year results, a 150 difficult to treat RA patients. They saw and they don't give me the incidence of d two t RA. It's generally about ten percent, maybe a little as high as fifteen percent in some studies.
Anyway, in their study, of the hundred 50 patients they followed, forty five percent of them of the difficult RA definition resolved, meaning they ultimately responded, but fifty percent persisted and five percent died. The resolved difficult to treat RA patients were younger, had more treatment changes, more IL six use, suggesting that maybe you should be treating them with newer drugs, especially if they're younger. Now, again, is the IL six use gonna be selective here? It tends to be used secondarily or or as third line in Japan, so I don't know how it's gonna pan out with the rest of the world. We need to wait and see.
Mortality was pretty in in in this cohort of a 150 difficult to treat patients, and as I said, was five percent, was predicted by comorbidity steroid escalation. Okay? And there the odds ratios was a comorbidity is three point five holder five three point five fold higher risk with comorbidities that were high, like three or more. And steroid escalation had a thirty two fold higher risk of mortality. Not good.
Takayasu's arteritis, we're sort of wrapping up now. If you give them biologics, will it matter? Will it help? In this cohort analysis of seventy five patients with Takayasu, were treated with conventional DMARDs, methotrexate, leflunomide, that kind of thing, azathioprine. Thirty five were given biologics, and they showed that that overall, a reduced, thickness artery thickness was seen in seventy three percent of their patients.
Thirty one percent decreased their arterial wall thickness by more than twenty five percent. And in the end, it was either the use of a biologic or other immunosuppressants like azathioprine that were able to reduce arterial wall thickness when they compared the results to those who just got conventional DMARDs. Makes a case for using biologics, and most of biologics used here were TNF inhibitors. Lastly, there's a study about pollution and the risk of lupus. I got two studies on the risk of lupus.
And one is that the study from the UK Biobank almost a half million people. And they actually did collect data on exposure to nitrous oxide and other kinds of pollutants. They showed that in the three hundred ninety nine patients who had lupus, they found a eighteen to twenty seven percent increased risk of lupus when they were exposed to these environmental pollutants. And it was even higher in lupus patients who had a genetic risk. I don't know what that's gonna be.
They didn't actually detail that in their report. But there's you know, we reported, like, three months ago about, polycyclic aromatic hydrocarbons also increasing the risk of lupus in the general population. And there's another report on RheumNow from yesterday about the pathogenesis of lupus, and it talks, again, about, environmental pollutants being important in the generation of the chemokine CXCL 13, which draw along which drives T cells to dry to to make more follicular helper T cells that will drive B cell activity, again related to, pollution. The other report comes from the nurses health study. This is from Karen Costenbatter's group.
And in this study, they lupus wasn't all that common. Amongst the Nurses Health Study, 200,000 nurses in two different, iterations of the Nurses Health Study, they had like four point five million years of observation, but only two hundred and twelve cases of new lupus. Right? These women tend to be a little bit older, I think. But nonetheless, that when they looked at their diets, the and they looked at the top turtle who were taking ultra processed food, a western diet, you know, Big Mac's, french fries, donuts.
These had an adjusted hazard ratio of one point five six, meaning fifty six percent higher risk of developing new onset incident lupus compared to those in the lowest turtle. So this is also soft drinks, and sugar sweetened products. So the idea is that, you know, there's this picture of of autoimmune disease now that has the environment as a strong predictor of risk. And it may be that in with certain genotypes that the risk gets even higher. Now you produce the autoimmune state, which is the preclinical state, which may evolve with a few other triggers into clinically manifest disease.
I think this kind of research is really framing our thinking, or maybe not just maybe confirming the way our thinking has been framed in the last few several years about how you get autoimmune disease. And the last report is on the cost effectiveness of biosimilars versus leflinomide. This is a Korean database that looked at, I think it was 26,000 patients and using Markov modeling, which is what how you assess the cost efficacy of a drug and whatnot. And here they looked at the lifetime cost of RA and the quality adjusted life years. They compared getting starting with leflunomide to starting with the bios the infliximab biosimilar CTP one three.
That's like Inflector and Rinflexis or the adalimumab biosimilar, ABP five zero one. And the cost lifetime cost of the disease was a 154,000 with leflunomide, a 152,000 with biosimilar infliximab, a 150 45,000 with biosimilar adalimumab. And the quality adjusted life years are all exactly the same. The point being that after after methotrexate, should you play around with conventional DMARDs or now with the cost of biosimilars becoming reasonable, can we go right to biosimilars? This is gonna challenge maybe how we treat our patients in the future.
Again, the great promise of biosimilars is going to be much cheaper, making it more widely available, and more patients being more aggressively treated. But, you know, in The United States, we've been very slow on the uptake of biosimilars. I think this data is going to help us make up our mind. That's it for this week on the podcast. Make sure you go to the website to check out these citations and more.
We'll talk to you next week. Take good care of yourself.
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