Maui Potpourri (2.13.2026) Save
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It's the 13th of February, 2026. This is the RheumNow podcast. Hi, I'm Jack Cush with RheumNow.live. That's right. We just finished RheumNow.live last weekend. It was a great meeting. Wish you were there. More on that at the end of this podcast.
This week I'm going to review for you some of the high points of the meeting that I was at in Dallas and hope that you can take some learning points from it as I did. We had a lot of great sessions. I want to begin with a session on diet and obesity management.
This featured Dr. Usma Haq from the Johns Hopkins Medical School, where she talked about diet, obesity, how obesity contributes to inflammation, how that's a problem for not just our patients but society. In the United States, 42% of the adult population is obese according to BMI criteria, and we do know that adipose tissue is a biologically active tissue that makes adipokines and other pro-inflammatory cytokines that basically have led us to understand that obesity is an inflammatory condition. Obesity is a prelude to the development of serious immunologic disorders, many of them. So avoiding it would help to avoid disorders, treating it will help to lessen the inflammatory load that drives many of these disorders.
While diet and exercise still are the mainstays of therapy, a lot has been revolutionized with the introduction of the incretins — that's the GLP-1 agonists and other variants of incretin therapy that have revolutionized not just the management of diabetes but certainly obesity, where it's not unreasonable to expect 20–30% body weight loss by taking these drugs. Since they have been around, the FDA has approved the GLP-1 drugs for non-insulin-dependent diabetes, obesity, as an adjunct to cardiovascular disease management, and as an adjunct to sleep apnea management. And we keep talking about these drugs in our disorders — in gout, in OA, in RA, in SLE — showing not just that they lose weight but that there's lessening of mortality risk, that the disease state itself is better managed.
This is all exciting. She reviewed a number of the studies and data that support the fact that weight loss really works, but that there's probably more than weight loss that's in play here. One of the most recent and very notable ones is the TOGETHER-PsA trial — results just released by Lilly as a press release. The actual data isn't going to be presented until they get to a big meeting, but this was a 36-week trial where patients with psoriatic arthritis — TOGETHER-PsA, psoriatic arthritis — and they're obese, either having a BMI greater than 30 or 27 with risk factors related to obesity, and they either received the IL-17 inhibitor which was approved for psoriatic arthritis, or ixekizumab plus tirzepatide, the GLP-1 agonist, as a combination therapy.
When they looked at the 36-week outcomes, the primary endpoint was achieving an ACR50 and having greater than 10% weight loss, and that was achieved by significantly more on the combination than on the single drug alone, ixekizumab. Moreover, when they just looked at ACR50 irrespective of weight loss, it was also very significant. And that is really very encouraging.
We know that tirzepatide and other GLP-1s are in clinical trials. She reviewed the data from other mainly observational trials — very little controlled trial data but mostly observational trials. Diabetics who were getting these drugs, looking at what happens when you took a GLP-1 drug versus an SGLT2 inhibitor for diabetes — not only what happened with weight loss but cardiovascular outcomes, disease outcomes — showing benefits in rheumatoid arthritis, in OA. That was a New England Journal article from last year, and also with lupus. So this is all very encouraging data. It was really an exciting session.
We're going to be hearing more and more about obesity and its management, especially in rheumatoid arthritis.
My next one, a follow-up to this lecture, was Susan Goodman from the Hospital for Special Surgery in New York. Susan, as you know, was the author of the ACR/AAHKS — that's the Association for Hip and Knee Surgeons — combined guidelines on how to manage patients with rheumatic disease in the perioperative period. So her lecture was on mitigating risk in rheumatology patients who are undergoing orthopedic surgery. It was really a great lecture. She went over the risks associated with PJI, perioperative joint infections, which for instance in rheumatoid arthritis is increased 50 to 80%. So rheumatoid patients undergoing major surgery have a higher risk of post-operative joint infections compared to those that don't have rheumatoid arthritis. The risk factors that contribute to PJI risk include the degree of obesity, operating room time, the length of surgery, whether or not there was staff
orius colonization, presence of comorbidity, disease activity, steroid use. But interestingly what was not a risk factor for PJI in many of these studies was biologics — biologics was not a risk factor. So as you know the ACR guidelines say that your patients can continue to take DMARD therapy — conventional DMARDs — that's right, methotrexate, azathioprine, hydroxychloroquine — do not need to be stopped for major surgery. All the data is gleaned inferentially from major surgeries, being hip and knee surgery, with almost no data about all those other surgeries you want to know about — eye surgery, skin surgery, gallbladder surgery, cochlear implant surgery — and all you can do in those situations is extrapolate from the hip and knee data and recommendations to your particular situation.
So, number one, continue the DMARDs, the conventional DMARDs. Number two, don't stop the steroids. The idea of stopping steroids is idiotic. Patients are going to flare. The idea of covering them with stress doses of steroids is also proven not to be necessary. Number three, JAK inhibitors probably need to be stopped. And that's not based on strong evidence, but that's expert opinion. And they also recommend that biologics be stopped. But the recommendation is that they be basically stopped for one dosing interval. So if a biologic is given every week, they need to be off it for a week and basically have the surgery done before their next dose would have normally occurred, right? So that they're on the downside of optimal drug levels for that particular biologic, and then you can restart really a week later. So basically you're going to be off for one dosing interval on biologics. Just think about whether it's a weekly drug, every other week drug, or every month drug, and that's how you manage it.
Same thing with JAK inhibitors. I think the recommendation there should be about one week being off the JAK inhibitor. Patients are going to flare if they're off for more than two weeks. I do recommend continuing patients on methotrexate and whatnot. You know, the surgeons are going to balk. They're going to yell and scream. They're going to give very firm directions on something they don't know about. Number one, point to the fact that this is a guideline developed by hip and knee surgeons, approved by their society. Or you can do what I do — I tell my patients, "Go to see the surgeon with a piece of paper and pencil, write down their recommendations, then come to me and I'll give them the right recommendation and the patient will do better."
What you don't want is a patient to be off for weeks and months — especially months — their disease is going to flare and that's going to screw up the healing. That's going to increase the risk of infection; inflammation drives risk for infection, and that is abundantly apparent.
And the last thing that she recommended was: what about intraarticular steroids? There's a lot of data about that and a lot of surgeons are very cavalier about injecting knees and then taking them to the OR. There's pretty good data that says that a patient who's had an intraarticular knee injection, or any intraarticular injection, within 3 months of surgery has a much higher risk of post-operative infection. It goes out to 6 months. So I say, and the guidelines say, that patients shouldn't have an intraarticular injection in the six months preceding a major surgery like hip or knee replacement. I think it's smart guidelines.
Next, in a session on psoriasis and psoriatic disease, we had Joe Merola, who is a rheumatologist-dermatologist and chief of dermatology — wait, he's a rheumatologist at UT Southwestern — and Dr. Merola addressed paradoxical reactions that are seen with the drugs that they use in dermatology that we use in rheumatology. You know, TNF inhibitors — patients who are taking them for rheumatoid arthritis develop TNF inhibitor-induced psoriasis. What? Don't TNF inhibitors treat psoriasis? But that's the paradoxical reaction story.
So what we know about TNF inhibitor-induced psoriasis is that in most cases the majority are palmoplantar psoriasis — palmoplantar pustulosis, palmoplantar disease, however you want to call it. The literature previously said you should probably just stop the drug. Dr. Merola went over the recent literature, which says you can continue the drug, change to another TNF inhibitor, or go off of it for a while. But the fact is palmoplantar disease is very difficult to control. Other forms of plaque psoriasis in the periphery you can often power through and continue the drug, or switch drug classes or drugs within the class. Palmoplantar disease is difficult enough that sometimes you actually have to stop the drug or treat them, and he showed some data about treating difficult patients with JAK inhibitors with good success. Again, this is all pretty much off-label, very much anecdotal, but there's good literature to
support that. The other interesting thing about this was if patients were on background methotrexate and they developed these — could they develop these paradoxical skin reactions? They absolutely could. Being on background methotrexate or other conventional DMARDs, would that protect against this? Doesn't seem to be the case. So he went into the biology of this, still not quite worked out to my satisfaction so I won't get into it. He did talk about eczema arising in patients who are taking the IL-17 inhibitors. It's been described with all of the IL-17 inhibitors although it's a very low incidence of about 6%. But it happens quite frequently and there again you probably have to hold the drug, stop the drug, switch to something else.
The IL-4/IL-13 targeted drug dupilumab has been associated with new onset psoriasis. Really kind of surprising. So again, a drug given for atopic and allergic diseases and whatnot has as an offshoot and a paradoxical reaction of producing either psoriasis or — most of the audience raised their hand when asked how many of you have seen someone with dupilumab-induced arthralgia or arthritis. Yes, that happens too. And it usually happens within the first few weeks of dupilumab. Certainly within the first six months, but it looked like it's more like within the first three months. And then when you stop the drug, it may take I don't know weeks if not months to resolve. So they may need symptomatic management or maybe even more aggressive than that management to treat the arthritis if you actually do have swollen joints.
Next, we had a great session on rheumatoid arthritis that started our convention on Saturday morning. Elena Myasoedova from the Mayo Clinic talked about mortality in RA. We know that it is significantly increased and while there's recent data since mainly 2000 showing that mortality rates in RA have declined, presumably because of more effective therapy, the introduction of biologics and targeted synthetics, the mortality rate has gone down. RA patients still have a 50% increased risk of mortality and 25% of them have sort of premature mortality risk.
She showed a number of factors that drive this but maybe the most important is seropositivity, especially anti-CCP but also rheumatoid factor, which in both cases either increases the rate 50 to 80% higher compared to those who are seronegative. We have seen this decline since 2000. We know mortality risk is driven by inflammation and disease activity. That's why long ago when Fred Wolfe did the first report — Wolfe and Choy — about methotrexate reducing mortality in RA and reducing cardiovascular events and cardiovascular deaths, it was all by control of inflammation, control of disease activity.
So, inflammation, disease activity — and then she made a really important point that extra-articular manifestations, whether it be vasculitis, episcleritis, ILD especially, and even nodules, those patients are at even greater risk for mortality and premature mortality. Turns out this increased mortality risk is driven by cardiovascular death or pulmonary death. And we do know RA patients are at higher risk for significant morbidity, more infections and infections that will kill you, and also pulmonary deaths unrelated to infection.
She did show good data about the role of steroids — that there wasn't good data to suggest that 5 milligrams of prednisone increased the risk of mortality, especially if you were under five milligrams. But she did show there is certain data, very significant data, that says if you're on 8 milligrams of prednisone or more a day, you have a much greater risk of mortality. And of course it has to do with how long you're on the steroid. So if you're on four milligrams of prednisone for a really long time and achieve 40 grams of steroid exposure, you're at higher risk. So cumulative dose — 40 grams of prednisone equivalents — that's not good.
And so I asked her the question, and she showed the data: what is the single best predictor of mortality when you first see someone with RA? I mean we know seropositivity, we know inflammation, but is there one biomarker? And she showed good data that frailty and measures of frailty was a very strong indicator of mortality risk and especially early mortality risk.
So the next lecture was by Kristen Deane from the University of Colorado at Denver, where she's working with a bunch of researchers who are very focused on RA pathogenesis, management of and interventions for preclinical RA, otherwise known as at-risk RA or clinically suspect arthralgia — CSA. And she started her lecture by saying RA does not begin in the joint. She said this to a room full of rheumatologists. 460 of us online and in the room probably went — what? It's a synovial disease. But she presented data that it really — and that's the title of her
lecture was the the you know the mucosal hypothesis to RA pathogenesis. The point being that RA begins by mucosal invasion either by environmental triggers or infection or by we don't know what. And that mucosa is primarily the lung, the periodontal tissues in the mouth and the GI tract. And it is these mucosal engagements that take someone who's probably at genetic risk and turns them into autoimmune disease because you have activation of all these immunologically active cells whether it's in the intestinal lamina or in the alveoli and macrophages there that then leads to the autoimmune state.
We have good evidence that inflammation in the lung is present in people who are asymptomatic but are CCP positive. No joint problems, no symptoms, no synovitis, they're just CCP positive. And first-degree relatives of RA patients are CCP positive. When they do bronchoalveolar lavage, they have lots of inflammation. They make in situ in the lung CCP antibodies. This is not good. This is where RA begins. This will in the future become maybe the target of therapy.
So there are a lot of things that contribute to this idea. The idea that smoking is a major contributor. The evidence of airway inflammation and CCP positive individuals locally produce CCP both from lavage fluid and also found in saliva. Um also significantly increasing the risk of progression to RA. And then there's IgA rheumatoid factor IgA CCP again further supporting the mucosal theory that secretory IgA from mucosal surfaces very much involved in the earlier stages and as important as the ones that we normally measure in clinic. And the last point that she made is that lung neutrophils are very much involved in NETosis and inducing NETs that are major drivers to early adaptive immunity.
Abnormalities drive alpha interferon and a lot of other signals that will be necessary to take someone from being at risk genetically to being at risk by having autoimmunity with autoantibodies present and now that's got to progress to chronic synovitis and clinically manifest disease. Um maybe it's those NETs, the NETosis that's going on driven by lung neutrophils, maybe intestinal neutrophils for that matter.
Great lecture by Kristen Deane. You might want to listen to the podcast. Dr. Sparks, Jeff Sparks from Brigham and Women's was there talking about advances in a fast-moving area. We covered that in September. A lot of good content. Jeff was a major influence for most of what we covered in September. His lecture was excellent. He talked about the 20-year risk of developing ILD in any RA patient is about 15% or one in six people with RA. And this is a bad prognostic sign, especially if they have rapid changes or significant changes in FVC over 6 months or over 12 months. High death rate, high complication rates.
The main pattern of interstitial lung disease in RA unlike all other CTDs — scleroderma, lupus, MCTD, dermatomyositis — though that's mainly NSIP, in RA it's primarily over two-thirds of the cases it's UIP, usual interstitial pneumonitis. Um in RA about somewhere between 20 and 40% are NSIP. The good thing about that — well it's not a good thing. UIP is bad. It's got a bad outcome. But there are things that we can do that's more specific for UIP and that mainly is using pirfenidone. You know, we have a lot of new anti-fibrotics, but pirfenidone efficacy looks like it's best in people with UIP, especially with RA.
He talked about the risk factors for developing RA-ILD, especially the MUC5B promoter variant which is highly influential in developing UIP disease, and then he went into all the other risk factors. And this is important because what do you do in RA — should you screen everybody for lung disease? The answer is no unless they have risk factors. The risk factors are increasing age, obesity, and the three S's. What are the three S's? Seropositivity, smoking, and sex meaning male. So males, seropositives, smokers — gigantic increase in ILD risk and UIP risk. The sooner you identify it, the sooner you're doing screening high-res CTs and doing those every six months and intervening with appropriate therapy.
And he went over the new guidelines as published by EULAR and the European Respiratory Society. Um, and I think that those were instructive. The good news is that you know control RA, treat to target, control synovitis, and when lung disease is either progressive or worsening or UIP you know then you're going to use immunosuppressives with an anti-fibrotic like nintedanib or the newer one nearast. And if you have UIP you should think about using pirfenidone, and if you're not going to prescribe these — as many rheumatologists are not — then you should probably be working with a lung immunologist who likes treating ILD.
He did make a point to go out of his way to answer that big question we all ask — what about methotrexate? And there's no risk of methotrexate causing ILD or worsening ILD based on good available evidence. And this is all in
spite of what your lung doctor is worried about — and they're worried about it because it's in their guidelines — stop the methotrexate, it's a contributor. It just happens to be wrong.
I'll end with a lecture I just gave here in Maui on seropositive versus seronegative RA. It's a topic I really like talking about. I'll lead by giving you something instructive from a recent Mayo Clinic paper also authored by Elena Masadova, John Davis, Cynthia Crowson, all those great people at the Mayo Clinic. They did a study on 1,373 patients with incident RA and that presentation — how many of them were seropositive and what did that mean?
Well, the good news is that 38% were seronegative by RF and CCP. But the bad news is in their study 37% were double positive for both. 12% were RF only and 13% were CCP only. And when they looked at the outcomes for these patients based on their serologies, the standout was the double positives. Oh boy, bad news. And this is why you should do multiple autoantibody testing in your rheumatoids. If they're double positive, they have a much higher risk of developing erosions and a much higher risk of having flares within the first year of their disease activity.
What about seropositivity — one or both or neither? Did it matter when it came to remission rates? You know what? It didn't. And then conversely I might say the idea that seronegative RA is milder and more likely to go into remission is in fact wrong.
So that's kind of what we covered. Seropositivity in the United States by any measure — about 20 million Americans. And we do know that in RA, 70% or more are seropositive for RF and/or CCP, but in early RA, in preclinical RA, it's like 20 to 40%. At the time of early RA diagnosis — first 6 months — it's usually less than 50%. It only gets up to 60% by around year two and 67–70% by year five or six. And that's also from that same Mayo Clinic paper.
So number one point in my lecture was that seronegative RA is not milder, is not easier. There's a lot that's unknown about it because it's often not studied and they're often not included in clinical trials. You need to know that at presentation most seronegatives have the same degree of activity — swollen joints, tender joints, disability, etc. — as do seropositives, and the reason is pretty obvious. Seropositives get referred earlier because you're more certain about the diagnosis. Seronegatives get referred later — there's uncertainty. So by the time they're referred they have more severe joints prompting the referral or the patient seeking medical attention. So it's important to know that again seronegative is not as mild.
So I would say overall seronegative is very misconsidered and often misdiagnosed, and if you look at the misdiagnosis numbers it's something like one-third to two-thirds of seronegatives are not properly diagnosed and with time will be correctly diagnosed. Ronan Kavanagh from Galway taught me that seeing a seronegative patient at every visit is your opportunity to consider a new diagnosis, and that's going to be prompted by a new development in their story, is it not.
We did cover the other antibodies that are used to diagnose RA, like carbamylated protein antibodies and 14-3-3η and ADA — these are seen in patients that are seronegative but they're low frequency. But the good part about those antibodies, if you want to use them, want to look at them, want to order them, is that they behave just like CCP and ACPA, meaning they're found 10 years before the disease. They're associated with more severe disease. They're associated with more X-ray progression. So they do have importance. I order them in select situations. I don't routinely order them in all people. I order rheumatoid factor and CCP and then consider other tests if I need to.
I don't want to have rheumatoid arthritis, but if I did, I think I'd want to be single positive seropositive because I'd be more easily and quickly referred to a rheumatologist. That's the data. I wouldn't want to be double positive — that's kind of ugly. Look for that. High titers of rheumatoid factor or CCP, or double positives, is a really bad subset as far as risk of extra-articular disease, cardiovascular, premature death. Yeah, they might get referred earlier, but there's so much bad I wouldn't want it.
Why would I want to be seronegative? The only reason I'd want to be seronegative is it gives me a chance at another diagnosis which maybe has a better outcome or may have even more specific therapy.
That's it for this week on the podcast. Tune in next week. Those of you who came to RheumNow Live, I hope you enjoyed it. Send me back your comments. Give me your suggestions for next year. It's going to be great. Next year, RheumNow Live is going to be February 6th and 7th in Dallas, Texas. Five minutes from the airport, just like this year. Hope you'll be there. Oh, the good news is all of you who missed it, you can sign up and register and get all the
content, all the lectures, look at all the videos, get all the downloads. It's now available on demand. If not like right now, it'll be available on demand within a week or so. So you can join the club. Talk to you next week. Bye-bye.
This week I'm going to review for you some of the high points of the meeting that I was at in Dallas and hope that you can take some learning points from it as I did. We had a lot of great sessions. I want to begin with a session on diet and obesity management.
This featured Dr. Usma Haq from the Johns Hopkins Medical School, where she talked about diet, obesity, how obesity contributes to inflammation, how that's a problem for not just our patients but society. In the United States, 42% of the adult population is obese according to BMI criteria, and we do know that adipose tissue is a biologically active tissue that makes adipokines and other pro-inflammatory cytokines that basically have led us to understand that obesity is an inflammatory condition. Obesity is a prelude to the development of serious immunologic disorders, many of them. So avoiding it would help to avoid disorders, treating it will help to lessen the inflammatory load that drives many of these disorders.
While diet and exercise still are the mainstays of therapy, a lot has been revolutionized with the introduction of the incretins — that's the GLP-1 agonists and other variants of incretin therapy that have revolutionized not just the management of diabetes but certainly obesity, where it's not unreasonable to expect 20–30% body weight loss by taking these drugs. Since they have been around, the FDA has approved the GLP-1 drugs for non-insulin-dependent diabetes, obesity, as an adjunct to cardiovascular disease management, and as an adjunct to sleep apnea management. And we keep talking about these drugs in our disorders — in gout, in OA, in RA, in SLE — showing not just that they lose weight but that there's lessening of mortality risk, that the disease state itself is better managed.
This is all exciting. She reviewed a number of the studies and data that support the fact that weight loss really works, but that there's probably more than weight loss that's in play here. One of the most recent and very notable ones is the TOGETHER-PsA trial — results just released by Lilly as a press release. The actual data isn't going to be presented until they get to a big meeting, but this was a 36-week trial where patients with psoriatic arthritis — TOGETHER-PsA, psoriatic arthritis — and they're obese, either having a BMI greater than 30 or 27 with risk factors related to obesity, and they either received the IL-17 inhibitor which was approved for psoriatic arthritis, or ixekizumab plus tirzepatide, the GLP-1 agonist, as a combination therapy.
When they looked at the 36-week outcomes, the primary endpoint was achieving an ACR50 and having greater than 10% weight loss, and that was achieved by significantly more on the combination than on the single drug alone, ixekizumab. Moreover, when they just looked at ACR50 irrespective of weight loss, it was also very significant. And that is really very encouraging.
We know that tirzepatide and other GLP-1s are in clinical trials. She reviewed the data from other mainly observational trials — very little controlled trial data but mostly observational trials. Diabetics who were getting these drugs, looking at what happens when you took a GLP-1 drug versus an SGLT2 inhibitor for diabetes — not only what happened with weight loss but cardiovascular outcomes, disease outcomes — showing benefits in rheumatoid arthritis, in OA. That was a New England Journal article from last year, and also with lupus. So this is all very encouraging data. It was really an exciting session.
We're going to be hearing more and more about obesity and its management, especially in rheumatoid arthritis.
My next one, a follow-up to this lecture, was Susan Goodman from the Hospital for Special Surgery in New York. Susan, as you know, was the author of the ACR/AAHKS — that's the Association for Hip and Knee Surgeons — combined guidelines on how to manage patients with rheumatic disease in the perioperative period. So her lecture was on mitigating risk in rheumatology patients who are undergoing orthopedic surgery. It was really a great lecture. She went over the risks associated with PJI, perioperative joint infections, which for instance in rheumatoid arthritis is increased 50 to 80%. So rheumatoid patients undergoing major surgery have a higher risk of post-operative joint infections compared to those that don't have rheumatoid arthritis. The risk factors that contribute to PJI risk include the degree of obesity, operating room time, the length of surgery, whether or not there was staff
orius colonization, presence of comorbidity, disease activity, steroid use. But interestingly what was not a risk factor for PJI in many of these studies was biologics — biologics was not a risk factor. So as you know the ACR guidelines say that your patients can continue to take DMARD therapy — conventional DMARDs — that's right, methotrexate, azathioprine, hydroxychloroquine — do not need to be stopped for major surgery. All the data is gleaned inferentially from major surgeries, being hip and knee surgery, with almost no data about all those other surgeries you want to know about — eye surgery, skin surgery, gallbladder surgery, cochlear implant surgery — and all you can do in those situations is extrapolate from the hip and knee data and recommendations to your particular situation.
So, number one, continue the DMARDs, the conventional DMARDs. Number two, don't stop the steroids. The idea of stopping steroids is idiotic. Patients are going to flare. The idea of covering them with stress doses of steroids is also proven not to be necessary. Number three, JAK inhibitors probably need to be stopped. And that's not based on strong evidence, but that's expert opinion. And they also recommend that biologics be stopped. But the recommendation is that they be basically stopped for one dosing interval. So if a biologic is given every week, they need to be off it for a week and basically have the surgery done before their next dose would have normally occurred, right? So that they're on the downside of optimal drug levels for that particular biologic, and then you can restart really a week later. So basically you're going to be off for one dosing interval on biologics. Just think about whether it's a weekly drug, every other week drug, or every month drug, and that's how you manage it.
Same thing with JAK inhibitors. I think the recommendation there should be about one week being off the JAK inhibitor. Patients are going to flare if they're off for more than two weeks. I do recommend continuing patients on methotrexate and whatnot. You know, the surgeons are going to balk. They're going to yell and scream. They're going to give very firm directions on something they don't know about. Number one, point to the fact that this is a guideline developed by hip and knee surgeons, approved by their society. Or you can do what I do — I tell my patients, "Go to see the surgeon with a piece of paper and pencil, write down their recommendations, then come to me and I'll give them the right recommendation and the patient will do better."
What you don't want is a patient to be off for weeks and months — especially months — their disease is going to flare and that's going to screw up the healing. That's going to increase the risk of infection; inflammation drives risk for infection, and that is abundantly apparent.
And the last thing that she recommended was: what about intraarticular steroids? There's a lot of data about that and a lot of surgeons are very cavalier about injecting knees and then taking them to the OR. There's pretty good data that says that a patient who's had an intraarticular knee injection, or any intraarticular injection, within 3 months of surgery has a much higher risk of post-operative infection. It goes out to 6 months. So I say, and the guidelines say, that patients shouldn't have an intraarticular injection in the six months preceding a major surgery like hip or knee replacement. I think it's smart guidelines.
Next, in a session on psoriasis and psoriatic disease, we had Joe Merola, who is a rheumatologist-dermatologist and chief of dermatology — wait, he's a rheumatologist at UT Southwestern — and Dr. Merola addressed paradoxical reactions that are seen with the drugs that they use in dermatology that we use in rheumatology. You know, TNF inhibitors — patients who are taking them for rheumatoid arthritis develop TNF inhibitor-induced psoriasis. What? Don't TNF inhibitors treat psoriasis? But that's the paradoxical reaction story.
So what we know about TNF inhibitor-induced psoriasis is that in most cases the majority are palmoplantar psoriasis — palmoplantar pustulosis, palmoplantar disease, however you want to call it. The literature previously said you should probably just stop the drug. Dr. Merola went over the recent literature, which says you can continue the drug, change to another TNF inhibitor, or go off of it for a while. But the fact is palmoplantar disease is very difficult to control. Other forms of plaque psoriasis in the periphery you can often power through and continue the drug, or switch drug classes or drugs within the class. Palmoplantar disease is difficult enough that sometimes you actually have to stop the drug or treat them, and he showed some data about treating difficult patients with JAK inhibitors with good success. Again, this is all pretty much off-label, very much anecdotal, but there's good literature to
support that. The other interesting thing about this was if patients were on background methotrexate and they developed these — could they develop these paradoxical skin reactions? They absolutely could. Being on background methotrexate or other conventional DMARDs, would that protect against this? Doesn't seem to be the case. So he went into the biology of this, still not quite worked out to my satisfaction so I won't get into it. He did talk about eczema arising in patients who are taking the IL-17 inhibitors. It's been described with all of the IL-17 inhibitors although it's a very low incidence of about 6%. But it happens quite frequently and there again you probably have to hold the drug, stop the drug, switch to something else.
The IL-4/IL-13 targeted drug dupilumab has been associated with new onset psoriasis. Really kind of surprising. So again, a drug given for atopic and allergic diseases and whatnot has as an offshoot and a paradoxical reaction of producing either psoriasis or — most of the audience raised their hand when asked how many of you have seen someone with dupilumab-induced arthralgia or arthritis. Yes, that happens too. And it usually happens within the first few weeks of dupilumab. Certainly within the first six months, but it looked like it's more like within the first three months. And then when you stop the drug, it may take I don't know weeks if not months to resolve. So they may need symptomatic management or maybe even more aggressive than that management to treat the arthritis if you actually do have swollen joints.
Next, we had a great session on rheumatoid arthritis that started our convention on Saturday morning. Elena Myasoedova from the Mayo Clinic talked about mortality in RA. We know that it is significantly increased and while there's recent data since mainly 2000 showing that mortality rates in RA have declined, presumably because of more effective therapy, the introduction of biologics and targeted synthetics, the mortality rate has gone down. RA patients still have a 50% increased risk of mortality and 25% of them have sort of premature mortality risk.
She showed a number of factors that drive this but maybe the most important is seropositivity, especially anti-CCP but also rheumatoid factor, which in both cases either increases the rate 50 to 80% higher compared to those who are seronegative. We have seen this decline since 2000. We know mortality risk is driven by inflammation and disease activity. That's why long ago when Fred Wolfe did the first report — Wolfe and Choy — about methotrexate reducing mortality in RA and reducing cardiovascular events and cardiovascular deaths, it was all by control of inflammation, control of disease activity.
So, inflammation, disease activity — and then she made a really important point that extra-articular manifestations, whether it be vasculitis, episcleritis, ILD especially, and even nodules, those patients are at even greater risk for mortality and premature mortality. Turns out this increased mortality risk is driven by cardiovascular death or pulmonary death. And we do know RA patients are at higher risk for significant morbidity, more infections and infections that will kill you, and also pulmonary deaths unrelated to infection.
She did show good data about the role of steroids — that there wasn't good data to suggest that 5 milligrams of prednisone increased the risk of mortality, especially if you were under five milligrams. But she did show there is certain data, very significant data, that says if you're on 8 milligrams of prednisone or more a day, you have a much greater risk of mortality. And of course it has to do with how long you're on the steroid. So if you're on four milligrams of prednisone for a really long time and achieve 40 grams of steroid exposure, you're at higher risk. So cumulative dose — 40 grams of prednisone equivalents — that's not good.
And so I asked her the question, and she showed the data: what is the single best predictor of mortality when you first see someone with RA? I mean we know seropositivity, we know inflammation, but is there one biomarker? And she showed good data that frailty and measures of frailty was a very strong indicator of mortality risk and especially early mortality risk.
So the next lecture was by Kristen Deane from the University of Colorado at Denver, where she's working with a bunch of researchers who are very focused on RA pathogenesis, management of and interventions for preclinical RA, otherwise known as at-risk RA or clinically suspect arthralgia — CSA. And she started her lecture by saying RA does not begin in the joint. She said this to a room full of rheumatologists. 460 of us online and in the room probably went — what? It's a synovial disease. But she presented data that it really — and that's the title of her
lecture was the the you know the mucosal hypothesis to RA pathogenesis. The point being that RA begins by mucosal invasion either by environmental triggers or infection or by we don't know what. And that mucosa is primarily the lung, the periodontal tissues in the mouth and the GI tract. And it is these mucosal engagements that take someone who's probably at genetic risk and turns them into autoimmune disease because you have activation of all these immunologically active cells whether it's in the intestinal lamina or in the alveoli and macrophages there that then leads to the autoimmune state.
We have good evidence that inflammation in the lung is present in people who are asymptomatic but are CCP positive. No joint problems, no symptoms, no synovitis, they're just CCP positive. And first-degree relatives of RA patients are CCP positive. When they do bronchoalveolar lavage, they have lots of inflammation. They make in situ in the lung CCP antibodies. This is not good. This is where RA begins. This will in the future become maybe the target of therapy.
So there are a lot of things that contribute to this idea. The idea that smoking is a major contributor. The evidence of airway inflammation and CCP positive individuals locally produce CCP both from lavage fluid and also found in saliva. Um also significantly increasing the risk of progression to RA. And then there's IgA rheumatoid factor IgA CCP again further supporting the mucosal theory that secretory IgA from mucosal surfaces very much involved in the earlier stages and as important as the ones that we normally measure in clinic. And the last point that she made is that lung neutrophils are very much involved in NETosis and inducing NETs that are major drivers to early adaptive immunity.
Abnormalities drive alpha interferon and a lot of other signals that will be necessary to take someone from being at risk genetically to being at risk by having autoimmunity with autoantibodies present and now that's got to progress to chronic synovitis and clinically manifest disease. Um maybe it's those NETs, the NETosis that's going on driven by lung neutrophils, maybe intestinal neutrophils for that matter.
Great lecture by Kristen Deane. You might want to listen to the podcast. Dr. Sparks, Jeff Sparks from Brigham and Women's was there talking about advances in a fast-moving area. We covered that in September. A lot of good content. Jeff was a major influence for most of what we covered in September. His lecture was excellent. He talked about the 20-year risk of developing ILD in any RA patient is about 15% or one in six people with RA. And this is a bad prognostic sign, especially if they have rapid changes or significant changes in FVC over 6 months or over 12 months. High death rate, high complication rates.
The main pattern of interstitial lung disease in RA unlike all other CTDs — scleroderma, lupus, MCTD, dermatomyositis — though that's mainly NSIP, in RA it's primarily over two-thirds of the cases it's UIP, usual interstitial pneumonitis. Um in RA about somewhere between 20 and 40% are NSIP. The good thing about that — well it's not a good thing. UIP is bad. It's got a bad outcome. But there are things that we can do that's more specific for UIP and that mainly is using pirfenidone. You know, we have a lot of new anti-fibrotics, but pirfenidone efficacy looks like it's best in people with UIP, especially with RA.
He talked about the risk factors for developing RA-ILD, especially the MUC5B promoter variant which is highly influential in developing UIP disease, and then he went into all the other risk factors. And this is important because what do you do in RA — should you screen everybody for lung disease? The answer is no unless they have risk factors. The risk factors are increasing age, obesity, and the three S's. What are the three S's? Seropositivity, smoking, and sex meaning male. So males, seropositives, smokers — gigantic increase in ILD risk and UIP risk. The sooner you identify it, the sooner you're doing screening high-res CTs and doing those every six months and intervening with appropriate therapy.
And he went over the new guidelines as published by EULAR and the European Respiratory Society. Um, and I think that those were instructive. The good news is that you know control RA, treat to target, control synovitis, and when lung disease is either progressive or worsening or UIP you know then you're going to use immunosuppressives with an anti-fibrotic like nintedanib or the newer one nearast. And if you have UIP you should think about using pirfenidone, and if you're not going to prescribe these — as many rheumatologists are not — then you should probably be working with a lung immunologist who likes treating ILD.
He did make a point to go out of his way to answer that big question we all ask — what about methotrexate? And there's no risk of methotrexate causing ILD or worsening ILD based on good available evidence. And this is all in
spite of what your lung doctor is worried about — and they're worried about it because it's in their guidelines — stop the methotrexate, it's a contributor. It just happens to be wrong.
I'll end with a lecture I just gave here in Maui on seropositive versus seronegative RA. It's a topic I really like talking about. I'll lead by giving you something instructive from a recent Mayo Clinic paper also authored by Elena Masadova, John Davis, Cynthia Crowson, all those great people at the Mayo Clinic. They did a study on 1,373 patients with incident RA and that presentation — how many of them were seropositive and what did that mean?
Well, the good news is that 38% were seronegative by RF and CCP. But the bad news is in their study 37% were double positive for both. 12% were RF only and 13% were CCP only. And when they looked at the outcomes for these patients based on their serologies, the standout was the double positives. Oh boy, bad news. And this is why you should do multiple autoantibody testing in your rheumatoids. If they're double positive, they have a much higher risk of developing erosions and a much higher risk of having flares within the first year of their disease activity.
What about seropositivity — one or both or neither? Did it matter when it came to remission rates? You know what? It didn't. And then conversely I might say the idea that seronegative RA is milder and more likely to go into remission is in fact wrong.
So that's kind of what we covered. Seropositivity in the United States by any measure — about 20 million Americans. And we do know that in RA, 70% or more are seropositive for RF and/or CCP, but in early RA, in preclinical RA, it's like 20 to 40%. At the time of early RA diagnosis — first 6 months — it's usually less than 50%. It only gets up to 60% by around year two and 67–70% by year five or six. And that's also from that same Mayo Clinic paper.
So number one point in my lecture was that seronegative RA is not milder, is not easier. There's a lot that's unknown about it because it's often not studied and they're often not included in clinical trials. You need to know that at presentation most seronegatives have the same degree of activity — swollen joints, tender joints, disability, etc. — as do seropositives, and the reason is pretty obvious. Seropositives get referred earlier because you're more certain about the diagnosis. Seronegatives get referred later — there's uncertainty. So by the time they're referred they have more severe joints prompting the referral or the patient seeking medical attention. So it's important to know that again seronegative is not as mild.
So I would say overall seronegative is very misconsidered and often misdiagnosed, and if you look at the misdiagnosis numbers it's something like one-third to two-thirds of seronegatives are not properly diagnosed and with time will be correctly diagnosed. Ronan Kavanagh from Galway taught me that seeing a seronegative patient at every visit is your opportunity to consider a new diagnosis, and that's going to be prompted by a new development in their story, is it not.
We did cover the other antibodies that are used to diagnose RA, like carbamylated protein antibodies and 14-3-3η and ADA — these are seen in patients that are seronegative but they're low frequency. But the good part about those antibodies, if you want to use them, want to look at them, want to order them, is that they behave just like CCP and ACPA, meaning they're found 10 years before the disease. They're associated with more severe disease. They're associated with more X-ray progression. So they do have importance. I order them in select situations. I don't routinely order them in all people. I order rheumatoid factor and CCP and then consider other tests if I need to.
I don't want to have rheumatoid arthritis, but if I did, I think I'd want to be single positive seropositive because I'd be more easily and quickly referred to a rheumatologist. That's the data. I wouldn't want to be double positive — that's kind of ugly. Look for that. High titers of rheumatoid factor or CCP, or double positives, is a really bad subset as far as risk of extra-articular disease, cardiovascular, premature death. Yeah, they might get referred earlier, but there's so much bad I wouldn't want it.
Why would I want to be seronegative? The only reason I'd want to be seronegative is it gives me a chance at another diagnosis which maybe has a better outcome or may have even more specific therapy.
That's it for this week on the podcast. Tune in next week. Those of you who came to RheumNow Live, I hope you enjoyed it. Send me back your comments. Give me your suggestions for next year. It's going to be great. Next year, RheumNow Live is going to be February 6th and 7th in Dallas, Texas. Five minutes from the airport, just like this year. Hope you'll be there. Oh, the good news is all of you who missed it, you can sign up and register and get all the
content, all the lectures, look at all the videos, get all the downloads. It's now available on demand. If not like right now, it'll be available on demand within a week or so. So you can join the club. Talk to you next week. Bye-bye.
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