UBER Rheumatology Ride (3.6.2026) Save
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It's March 6, 2026. This is the RheumNow podcast. Hi, I'm Dr. Jack Cush with RheumNow. I'm going to be your rheumatology Uber driver. And on this trip, we're going to discuss some of your favorite things and a few of my favorite things on our way to your destination. By the way, where was that again? Just punch it in. And let's let autopilot take us there. And in the meantime, I'll just talk up a storm. Don't you love it when the Uber driver just won't shut up? Well, that's what's going to happen here.
So, we're going to begin with joint hypermobility. In fact, of these first three reports, one of them is my favorite evaluation. You're going to have to figure it out. Is it joint hypermobility? Well, this was from Clinical Rheumatology. They did a cross-sectional study. I think this was done in Kuwait. They studied 256 young adults. I think they were all either college students. I think they were medical students. And they did, you know, Beighton scores on them and tried to find out how many had hypermobility. And then what was the incidence of other features? Well, of the 256 adults, three-quarters of them were female. They found hypermobility in 42%. And they based this on the Beighton scores, you know, those like six or eight maneuvers that you do, including, you know, elbow hyperextension, knee hyperextension, bending your thumb back, etc. And they found that of these ones who met the joint hypermobility at the lowest level, 88% had some form of musculoskeletal pain, most of that chronic — and that meaning over time, not like — I don't think they really had sustained chronic — 38 did have acute musculoskeletal pain. And they found that musculoskeletal pain was higher in those who had Beighton scores between four and six out of a potential of nine points.
So again, the takeaway here is it's a young person's disease. It is far more likely to occur in women and you got to do the maneuvers and suspect this. You know, if I'm seeing someone who I think has juvenile or adolescent fibromyalgia, I'm doing these Beighton maneuvers to see if they don't also have hypermobility. I think it's a good idea.
I love this report from Denmark about open access arthralgia clinics. I thought this was great. You know what? I'm going to hold that until the end because I want to talk a lot about that.
My next report is on upadacitinib — an open label trial of upadacitinib being used in Behçet's. Now I've seen a little bit of that done. I don't know that I've ever done it. I like managing Behçet's. I think we have some better drugs other than steroids. We don't want to use too much steroids there. Anyway, in this open label experience in 27 Behçet's patients, average age was 36 years. The activity score — the BDCAF score — was four out of a two to seven range. At six months, response was seen in 85%, 16 having complete response, seven having partial response, with substantial reductions in BDCAF scores, CRP, sed rate, steroid dose, all by week 24. Of that total cohort of 27, three relapsed during the follow-up period.
This is encouraging. You know, I think I'd like to see a controlled trial done of this because I've seen way too many people get TNF inhibitors for Behçet's, which I don't think works at all for the joint and skin manifestations. For the eye manifestations, yeah, I think there is good data for inflammation, but honestly, I'm not a big TNF inhibitor believer there. I'd like to see what a JAK inhibitor would do in a clinical trial — well-designed, controlled, either active controlled or placebo controlled trial. Please, someone should do it.
A retrospective analysis of 381 patients with EGPA. Let me say it again — 381. Again, this is a pan-European collective experience over a six-year period from a bunch of different countries. Out of the 381, they classified them as either 36 with prodromal EGPA, 220 with eosinophilic phase, and 125 with vasculitic. The point here was that half of them did receive biologics. You were more likely to get it if you had the vasculitic phase or vasculitic predominance of EGPA. Those people had the most comorbidities. They had more clinical manifestations and they were more likely to be hospitalized. All the people — everybody — was on steroids, and again, biologics were more likely to be used in those with the vasculitic stage.
A report from Journal of Rheumatology looked at the IBD-is-there-arthritis question that we have discussed in the past. Again, depends on how you're looking. In the past, when we'd looked at people who were routinely screened — either arthritis patients with camera studies or bowel studies — they found a fair number of occult IBD, right, up to 10 to 20%. Here they're looking at 1,553 IBD patients. About 80% with Crohn's disease, over 300 with ulcerative colitis. And these patients were started on either biologics for IBD or a JAK
inhibitor. So they all had 5 years or more of symptoms. And overall, what percentage do you think developed musculoskeletal symptoms? They didn't have musculoskeletal symptoms going in. That was an exclusion. Over time, 5 plus years followup, it's almost 7% — 6.8%. And one-third of those, which is really only, you know, 2 and a half%, less than 2 and a half%, developed or were diagnosed with axSpA. So occult axSpA in well-diagnosed IBD less common than occult IBD in well-diagnosed axSpA. Predictors of developing disease was being B27 positive, where it was almost a four-fold higher risk, and having higher ulcerative colitis activity scores. About a 57% increased risk, a hazard ratio of 1.57. It wasn't higher with the Crohn's disease activity score — the CDAI — that was not a predictor. So why only in ulcerative colitis and not in Crohn's? Hm. Anyway, the point is that it does occur, right? Arthritis does occur, and maybe that's a number of consults you should be getting from your GI colleagues.
We know that IL-23 inhibitors are a big deal in IBD. What about in GCA? We've had mixed reports about IL-17s in GCA and PMR — failing in GCA in phase 3 trials but showing some positive early signals for PMR. It's still confused. We don't know. But IL-23, what's the story with that? Well, here is a pilot study of 53 GCA patients. 35 were given risankizumab, the IL-23 inhibitor, and 18 were given placebo. At week 28, no better outcomes with the IL-23 inhibitor. Same amount of glucocorticoid-free remissions, 35 to 40%. Also similarly flare rates, 31 or 39%. This doesn't look favorable for IL-23 inhibition as a future therapy for giant cell arteritis.
Diacerin. Have you heard about diacerin? I mean, ever since I was a fellow I've heard reports about diacerin and wondered why it wasn't being used in the United States or in Canada. A JAMA Internal Medicine article reported the results of diacerin, an oral IL-1 beta inhibitor, compared to placebo in a randomized controlled trial of knee OA — but they had to have inflammation to get in, measured in a few different ways, and they had to have knee pain. So 262 patients, the primary endpoint was at 6 months. Almost 90% completed the trial. And compared to placebo, no real difference in knee pain — that was the primary endpoint. They had the same amount of adverse events, 42%. Most of that being GI symptoms. GI symptoms were more common with diacerin, 42%, than placebo, 25%. Again, this drug is approved. The study was done in Australia, where it is approved. It's commonly used in Southeast Asia and a few European countries. I think it's available in Mexico. Why not the United States? Well, it was never developed. I think mainly because IL-1 is not its sole mechanism of action. And secondly, it's got a lot of GI side effects — diarrhea in half the patients, etc. I think those who evaluated this, and also maybe there was a patent issue, who knows? But anyway, we're not going to see that in the United States. It is available worldwide, but it doesn't look like it works very well in osteoarthritis. Hence, don't do it.
What should you do in osteoarthritis? Well, you always recommend weight loss and exercise and whatnot. Does weight loss work? Yes, we know it works, right? Does exercise work? Uh-oh. That's this report. A meta-analysis of five review studies, 8,600 patients in 28 trials, shows little or no proof that exercise benefits OA outcomes. In some of the studies, exercise had a small, very short-term effect compared to placebo or no treatment at all, but it was very small, very short term, almost not even worth mentioning. And there's moderate evidence suggesting no effect on hip pain and small effects on hand OA.
Now does this surprise you? I mean, I know you recommend exercise, but I think for exercise to work in OA — especially hip and knee — I think they'd have to lose weight. I think they'd have to get substantially stronger. Do most of your patients who do take your advice, who do exercise, do they really get stronger? I thought in my clinic that I would post a gigantic sign out in the waiting room about, you know, the goal this year is to be strong. That's the goal. The stronger you are, the less pain you're going to have, the more you're going to be able to move. And making that my primary message really enforces this idea of weight loss and getting stronger and exercising. Because I think it's a lot of lip service. Now these are trials that were done — hopefully it was more than lip service — but this was a big disappointment.
More data about gout comes from the NHANES, a national survey that's done periodically in the United States, looked at the association of RA and gout. I don't know about you, but I've been teaching for years — yes, mostly to primary care audiences — that you can't have RA and
gout. That they are the inverse of each other. And if you think it's RA and gout, well, order a uric acid, order a rheumatoid factor or CCP, and the lab will decide for you — because how good are people at making a diagnosis of RA and gout if they're not rheumatologists?
But if you're a rheumatologist, you can say, "Wait, wait, wait, wait. I have seen people" — and yes, I know there is this survey, and now you're relying on what patients are told and what they believe; these are not backed up by chart reviews. But nonetheless, according to this NHANES survey, gout prevalence is increased in RA patients compared to non-RA controls. Gout is found in 10.3% of RA patients and less than 5% of controls, that being highly significant. Moreover, over time, the risk of gout has gone up in RA patients, and RA seems to be an independent risk factor for gout with an odds ratio of 2.67, strongest for seronegative RA.
I got to say there's still some confusion here. Seronegative RA — could that not be gout? How do they know it was RA? RA is stable over time, but the risk of gout in RA is increasing and trending over time. Well, isn't the odds of gout increasing over time in association with the obesity epidemic? Yeah, there's still some cloudiness here. Yes, if you're an expert rheumatologist, you can diagnose both. Although I do like the idea of letting the labs make up part of the decision, or letting imaging make up part of the decision, or ultrasound, if you will — because they're kind of different, are they not, by those parameters.
Nonetheless, I do think that it's worth considering that diagnosis. What else can you do in gout patients? This is a meta-analysis of eight studies, 2,600 gout patients, showing that predictors of future acute gout attacks would be — and you know what, they didn't put uric acid in this paper, I don't know why — but they did go on and on and on about an elevated neutrophil-to-lymphocyte ratio, NLR, and the same for the platelet-to-lymphocyte ratio, the PLR. The NLR number should be like greater than four. I don't know what the PLR cutoff is, but if those numbers are high, your patients are probably at higher risk for a gout attack coming up soon.
We're going to end with a whole lot of lupus studies and then open access. So, the prevalence of lupus in Australia — what do you think it is? United States, I know what the Lupus Foundation says: it's 5 million, 95 million. They're equating ANA positivity with lupus. That's wrong. You know, most of the epidemiologic studies in the United States say it's somewhere between 219,000 and 299,000 in the United States who have lupus.
In Australia, which has one — what is that, one-thirteenth the population of the United States — the prevalence of lupus is 26,788: 16,000 certain, 10,000 less certain. So the incidence between 2010 and 2022 went from 77 to 127 per 100,000, and that's looking at certain diagnoses. About half of the patients with lupus in Australia are being managed in an outpatient setting. These numbers, by the way, are on par with the same kind of incidence rates in the United States.
Arthritis Care and Research had an important study this week about cause of death in lupus. It's a CDC study that looked at death certificates over a 5-year period where they found almost 15,000 SLE deaths. About 43% of the death certificates listed lupus as the primary cause of death. When you look at the mortality rate per million, it was about six times higher in females than males — almost 6 versus 1.1 in females versus 1.1 in males. It's over 10 — 10.7 per million in African Americans.
What are the causes of death? Heart disease was double the rate of cancer and double the rate of COVID, and all of this occurred during the COVID era, so that's why they're using that as a reference point. A lot of lupus patients must have died from COVID.
Hydroxychloroquine — a report from British Columbia showing that adherence to hydroxychloroquine in either RA or lupus was associated with a significantly lower risk of hospitalization. Again, you might have remembered I wrote an article within the last four months about how everybody with RA should be on hydroxychloroquine as part of a combination, because it has the same benefits in RA that it does in lupus — where we know it lowers glucose and insulin resistance, and it lowers lipids, and it lowers cardiovascular events, and so on, and is better for pregnancy outcomes. Again, the same thing holds true, I think, in RA. And here's more evidence of that.
Other lupus news: the FDA this week granted fast-track designation to Johnson and Johnson's FcRn drug — the neonatal Fc receptor blockade called nipocalimab. As you know, that's been studied in Sjögren's and has been studied in RA. Looked good in Sjögren's in phase 2, not so plus-plus-minus in RA. It's a positive phase 2. The phase 2 JASMINE study looked good, and now it's in
a phase three trial in lupus. So again, it's fast-tracked for its use in lupus. It'll be interesting to see how that comes out.
We also had a nice review article written by Dr. Irvy Zala. Dr. Zala is a resident at Northwestern who wrote a nice review of calcineurin inhibitors in lupus nephritis. Most of us don't use calcineurin inhibitors yet. There's three out there. There's cyclosporin — Arie Kavanagh and I and Peter Lipsky were using that back in our lupus clinic at Parkland back in the late 80s in our difficult cases. Tacrolimus is out there and more recently FDA approved is voclosporin. As you know, the lupus nephritis guidelines talk about the use of calcineurin inhibitors. If you have stage three or four disease, they want you to be on triple therapy that includes steroids, mycophenolate, and either belimumab or a calcineurin inhibitor. But if you have pure stage five, the lupus guidelines say that you should get steroids, mycophenolate, and a calcineurin inhibitor, but not if the eGFR is less than 45 per minute. Meaning if they're CKD 3B or worse, you probably don't want to use it because of the chance of nephrotoxicity. So again, these are important adjuncts that we should be using. As you know, the package insert says that the indication for use of the lone calcineurin inhibitor FDA approved — voclosporin — is in the treatment of adults with lupus nephritis as part of a regimen that involves an immunosuppressant.
And lastly, I got a few more things. Open access arthrology clinics. This was a great report coming out of Denmark, and in this study — where are my — where's my data — a single center retrospective study of a 5-year experience, and what they were trying to do was facilitate referrals of arthralgia patients from primary care to rheumatologists or to the early arthritis clinic. They've inserted this in between the primary care and the early arthritis clinic to make these fast-track 10-minute evaluations done by experienced rheumatologists. Over a 5-year period, they did 761 open access arthralgia clinic evaluations. And again, they just get referred with or without labs, with or without imaging. In this 5 years, 20% of the patients were referred directly to the early arthritis clinic and 80% were discharged. Of the ones that went to the early arthritis clinic, 11% had inflammatory arthritis and half of them had RA. A total of 32 new onset RA patients were diagnosed, with one in five — or 20% — of them coming from the open access arthrology clinic.
Why do I like this? I did this as a screening tool to get patients into a study. I was trying to recruit for OA of the knee for an NIH study — the glucosamine GAIT study. And we did these basically open access arthralgia clinics. We advertised it in the paper as free arthritis clinic evaluations. No diagnoses or prescriptions would be provided, meaning they're going to get a fast evaluation. And we saw — I think we did six of these — we saw like 60 people every afternoon and they got about a five-minute evaluation, and we saw the same kind of results. Except I was able to recruit like 80 or 90 people for my OA study, but we had a bunch of people that got referred to our early arthritis clinic or to our regular rheumatology clinic, and then we referred people to other areas for other things.
The point being: why aren't we doing this in practice? When I was teaching about the advantages of doing an early arthritis clinic, I had lots of positive responses, but nobody did it because it really means that you would have to open up a slot and leave a slot empty for Wednesday afternoon that your primary care people could refer to. Maybe two slots during the week, two hours each. My point was leave them open and then you're going to fill them, because there's always people calling for appointments, and if you don't fill them then you're going to see someone with fibromyalgia earlier than 6 months. But if it's a new early RA referral, great; if it's a new onset arthralgia, even better. And by the way, these are fast evaluations. You're great at pattern recognition. I think everybody should be doing this. Congratulations to the Danish investigators who did this.
A few more things. One, if you have dermatology colleagues, make sure you refer them to the Derm on RheumNow podcast. I do that monthly. You can see it on the website, you can see it on YouTube, it's on our podcast channels. It's basically a compilation of all the dermatology content for the dermatologist that I have already shared with you, because you're a rheumatologist or you're rheum-interested.
Another thing — RheumNow Live is done. But if you missed it, now's the time to get it. Even still, you can now get RheumNow Live on demand by going to RheumNow.live. It's 2 days of the best and most recent clinical updates with the best faculty. You can
download all the materials. You can view all the slides. All the sessions. You can listen to them or watch them. You can do it whenever you want. There are pre-learn downloads. There are actual lecture downloads. Again, all of it can be accessed either in the show notes or by going to RheumNow.live.
One more. I've been holding this one back for a few weeks because we were so busy, but I want to get to it today. This is coming from Ask Cush — anything from the website. You can go to the website, lower right-hand corner, click on there and dictate or record your case and I'll discuss it here on the podcast.
This one comes from Gita Fathi. Gita is a rheumatologist in Camaro, California, and she sent me a case that she knew I couldn't resist. It's about Still's disease. A 42-year-old thin woman diagnosed with Still's disease — it looks like 20 years ago. Onset of rash — didn't say what kind — sore throat, arthritis, fevers up to 103, hepatosplenomegaly, lymphadenopathy. We see a prodromal sore throat, seronegative for RF and ANA, ferritin at times greater than 40,000, and evidence of transaminitis. You'd say, well, it sounds like Still's disease.
Well, when she plugged it in, I said, well, go back and plug it into StillsNow.com, put it in the Still's calculator. She said it didn't meet the Cush criteria for Still's disease, but it did meet the Yamaguchi criteria. And we all know that the Yamaguchi criteria are very good. And you can imagine what I might say about the Cush criteria.
But nonetheless, this patient had by my criteria eight points — you need 10 points. If the patient had the classic rash, the evanescent salmon-pink rash, then she'd be at nine points. If she had the quotidian fever that was classic, she'd have, again, maybe 10 points. If the arthritis was more than one joint and it was a polyarthritis, it might have met Cush criteria. But that's not why she's writing me. She's writing me because the patient is difficult to treat — meaning that in spite of being treated with anakinra, Actemra, anakinra in double dose, Actemra in high doses, canakinumab, methotrexate, infliximab, and even a JAK inhibitor, tofacitinib — she cannot get the patient's steroids below 20 milligrams a day. And that was the question.
So more recently the patient has only been able to get down to like 25, sometimes 20 milligrams of prednisone a day while on methotrexate 15 a week plus canakinumab 300 every other week. And again, they tried replacing the methotrexate with tofacitinib at 10 once a day or 10 twice a day — still unable to wean the steroids.
Anyway, my answer back to Gita was: number one, does it meet the criteria? Number two, when you encounter what you think is difficult-to-treat Still's disease, my first go-to is to call someone who treats a lot of Still's disease. And by the way, that includes the pediatric rheumatologists, who are way better at this than we adults, because they see it all the time. And pediatric Still's is the same disease as adult Still's. Or call a rheumatologist in your community that you know sees a lot of Still's. Or if you don't know, call me or send me an email like Gita did, and I'll always respond back to you or present it here on the podcast.
But when you get difficult-to-treat Still's disease and they're really not behaving as they should when you use your strongest drugs, then the first thing I do is genetic testing — meaning I'm going to send off a panel of genes that look for autoinflammatory conditions.
So I said to Gita: in my clinic I've seen hundreds of referrals from rheumatologists from all over the country, all over the world. And of all the referrals I've ever gotten — and these coming from very smart, great rheumatologists like yourself — only 40% have Still's disease by criteria, by my criteria or Yamaguchi. I don't feel bad about that, because if I were working with Raphaela Goldbach-Mansky and Dan Kastner in their autoinflammatory clinic at the NIH, we would know that only 60% of their autoinflammatory patients have a defined diagnosis, and there's 40% that we're just not going to know — but we're going to manage them.
So, get a gene panel. Maybe you get another insight as to what this could be. And the algorithm here begins with: are you treating systemic disease, or are you treating arthritis? If you're treating arthritis with Still's, then treat it as if it's RA. Are you treating systemic disease — and by that I mean high fevers, evanescent rashes, serositis, high white cell counts, very high sed rates and CRP? I don't hang my hat on ferritin. Only 50% of patients have an elevated ferritin, and only 10% have that hyperferritinemia that you all think is so pathognomonic when it really isn't. But it's great if I see hyperferritinemia — I'm worried about MAS. And yes, Still's is a cause of MAS.
So, are you treating systemic disease? And if you do, European and PRINTO guidelines and ACR guidelines say use an
IL-1 inhibitor or IL-6 inhibitor first. And that steroids, you know, aren't the first line therapy.
Okay. And in my experience again it's IL-1 or IL-6 often in high doses right — maybe higher than what you're prepared to use — not 100 once a day of anakinra but maybe 100 twice a day or 200 QHS, because IL-1 is secreted at night when they're asleep.
Same thing with IL-6, the TENDER trial. Use doses, and this is in kids with systemic JIA, use doses up to 12 milligrams per kilogram, and you're playing around with four or maybe eight. Again, I wouldn't want to be on 12 for a long period of time, but at least to get control of disease.
And then I like using JAK inhibitors, but we need to see clinical trials of JAK inhibitors. My experience has been positive, and everybody's probably on a background of methotrexate if they have problematic disease.
I wrote down — I don't think there's any value in trying for systemic disease — trying abatacept, cyclosporine, or even more steroids. For me, the jury's out about adjunctive use of azathioprine, hydroxychloroquine, or a calcineurin inhibitor.
Anyway, you got a case, go to the website, bottom left-hand corner, click on Ask Cush Anything and we'll discuss your case in the future here on the podcast. Oh, we've arrived at your destination. The bill is as shown on the meter. Take care.
So, we're going to begin with joint hypermobility. In fact, of these first three reports, one of them is my favorite evaluation. You're going to have to figure it out. Is it joint hypermobility? Well, this was from Clinical Rheumatology. They did a cross-sectional study. I think this was done in Kuwait. They studied 256 young adults. I think they were all either college students. I think they were medical students. And they did, you know, Beighton scores on them and tried to find out how many had hypermobility. And then what was the incidence of other features? Well, of the 256 adults, three-quarters of them were female. They found hypermobility in 42%. And they based this on the Beighton scores, you know, those like six or eight maneuvers that you do, including, you know, elbow hyperextension, knee hyperextension, bending your thumb back, etc. And they found that of these ones who met the joint hypermobility at the lowest level, 88% had some form of musculoskeletal pain, most of that chronic — and that meaning over time, not like — I don't think they really had sustained chronic — 38 did have acute musculoskeletal pain. And they found that musculoskeletal pain was higher in those who had Beighton scores between four and six out of a potential of nine points.
So again, the takeaway here is it's a young person's disease. It is far more likely to occur in women and you got to do the maneuvers and suspect this. You know, if I'm seeing someone who I think has juvenile or adolescent fibromyalgia, I'm doing these Beighton maneuvers to see if they don't also have hypermobility. I think it's a good idea.
I love this report from Denmark about open access arthralgia clinics. I thought this was great. You know what? I'm going to hold that until the end because I want to talk a lot about that.
My next report is on upadacitinib — an open label trial of upadacitinib being used in Behçet's. Now I've seen a little bit of that done. I don't know that I've ever done it. I like managing Behçet's. I think we have some better drugs other than steroids. We don't want to use too much steroids there. Anyway, in this open label experience in 27 Behçet's patients, average age was 36 years. The activity score — the BDCAF score — was four out of a two to seven range. At six months, response was seen in 85%, 16 having complete response, seven having partial response, with substantial reductions in BDCAF scores, CRP, sed rate, steroid dose, all by week 24. Of that total cohort of 27, three relapsed during the follow-up period.
This is encouraging. You know, I think I'd like to see a controlled trial done of this because I've seen way too many people get TNF inhibitors for Behçet's, which I don't think works at all for the joint and skin manifestations. For the eye manifestations, yeah, I think there is good data for inflammation, but honestly, I'm not a big TNF inhibitor believer there. I'd like to see what a JAK inhibitor would do in a clinical trial — well-designed, controlled, either active controlled or placebo controlled trial. Please, someone should do it.
A retrospective analysis of 381 patients with EGPA. Let me say it again — 381. Again, this is a pan-European collective experience over a six-year period from a bunch of different countries. Out of the 381, they classified them as either 36 with prodromal EGPA, 220 with eosinophilic phase, and 125 with vasculitic. The point here was that half of them did receive biologics. You were more likely to get it if you had the vasculitic phase or vasculitic predominance of EGPA. Those people had the most comorbidities. They had more clinical manifestations and they were more likely to be hospitalized. All the people — everybody — was on steroids, and again, biologics were more likely to be used in those with the vasculitic stage.
A report from Journal of Rheumatology looked at the IBD-is-there-arthritis question that we have discussed in the past. Again, depends on how you're looking. In the past, when we'd looked at people who were routinely screened — either arthritis patients with camera studies or bowel studies — they found a fair number of occult IBD, right, up to 10 to 20%. Here they're looking at 1,553 IBD patients. About 80% with Crohn's disease, over 300 with ulcerative colitis. And these patients were started on either biologics for IBD or a JAK
inhibitor. So they all had 5 years or more of symptoms. And overall, what percentage do you think developed musculoskeletal symptoms? They didn't have musculoskeletal symptoms going in. That was an exclusion. Over time, 5 plus years followup, it's almost 7% — 6.8%. And one-third of those, which is really only, you know, 2 and a half%, less than 2 and a half%, developed or were diagnosed with axSpA. So occult axSpA in well-diagnosed IBD less common than occult IBD in well-diagnosed axSpA. Predictors of developing disease was being B27 positive, where it was almost a four-fold higher risk, and having higher ulcerative colitis activity scores. About a 57% increased risk, a hazard ratio of 1.57. It wasn't higher with the Crohn's disease activity score — the CDAI — that was not a predictor. So why only in ulcerative colitis and not in Crohn's? Hm. Anyway, the point is that it does occur, right? Arthritis does occur, and maybe that's a number of consults you should be getting from your GI colleagues.
We know that IL-23 inhibitors are a big deal in IBD. What about in GCA? We've had mixed reports about IL-17s in GCA and PMR — failing in GCA in phase 3 trials but showing some positive early signals for PMR. It's still confused. We don't know. But IL-23, what's the story with that? Well, here is a pilot study of 53 GCA patients. 35 were given risankizumab, the IL-23 inhibitor, and 18 were given placebo. At week 28, no better outcomes with the IL-23 inhibitor. Same amount of glucocorticoid-free remissions, 35 to 40%. Also similarly flare rates, 31 or 39%. This doesn't look favorable for IL-23 inhibition as a future therapy for giant cell arteritis.
Diacerin. Have you heard about diacerin? I mean, ever since I was a fellow I've heard reports about diacerin and wondered why it wasn't being used in the United States or in Canada. A JAMA Internal Medicine article reported the results of diacerin, an oral IL-1 beta inhibitor, compared to placebo in a randomized controlled trial of knee OA — but they had to have inflammation to get in, measured in a few different ways, and they had to have knee pain. So 262 patients, the primary endpoint was at 6 months. Almost 90% completed the trial. And compared to placebo, no real difference in knee pain — that was the primary endpoint. They had the same amount of adverse events, 42%. Most of that being GI symptoms. GI symptoms were more common with diacerin, 42%, than placebo, 25%. Again, this drug is approved. The study was done in Australia, where it is approved. It's commonly used in Southeast Asia and a few European countries. I think it's available in Mexico. Why not the United States? Well, it was never developed. I think mainly because IL-1 is not its sole mechanism of action. And secondly, it's got a lot of GI side effects — diarrhea in half the patients, etc. I think those who evaluated this, and also maybe there was a patent issue, who knows? But anyway, we're not going to see that in the United States. It is available worldwide, but it doesn't look like it works very well in osteoarthritis. Hence, don't do it.
What should you do in osteoarthritis? Well, you always recommend weight loss and exercise and whatnot. Does weight loss work? Yes, we know it works, right? Does exercise work? Uh-oh. That's this report. A meta-analysis of five review studies, 8,600 patients in 28 trials, shows little or no proof that exercise benefits OA outcomes. In some of the studies, exercise had a small, very short-term effect compared to placebo or no treatment at all, but it was very small, very short term, almost not even worth mentioning. And there's moderate evidence suggesting no effect on hip pain and small effects on hand OA.
Now does this surprise you? I mean, I know you recommend exercise, but I think for exercise to work in OA — especially hip and knee — I think they'd have to lose weight. I think they'd have to get substantially stronger. Do most of your patients who do take your advice, who do exercise, do they really get stronger? I thought in my clinic that I would post a gigantic sign out in the waiting room about, you know, the goal this year is to be strong. That's the goal. The stronger you are, the less pain you're going to have, the more you're going to be able to move. And making that my primary message really enforces this idea of weight loss and getting stronger and exercising. Because I think it's a lot of lip service. Now these are trials that were done — hopefully it was more than lip service — but this was a big disappointment.
More data about gout comes from the NHANES, a national survey that's done periodically in the United States, looked at the association of RA and gout. I don't know about you, but I've been teaching for years — yes, mostly to primary care audiences — that you can't have RA and
gout. That they are the inverse of each other. And if you think it's RA and gout, well, order a uric acid, order a rheumatoid factor or CCP, and the lab will decide for you — because how good are people at making a diagnosis of RA and gout if they're not rheumatologists?
But if you're a rheumatologist, you can say, "Wait, wait, wait, wait. I have seen people" — and yes, I know there is this survey, and now you're relying on what patients are told and what they believe; these are not backed up by chart reviews. But nonetheless, according to this NHANES survey, gout prevalence is increased in RA patients compared to non-RA controls. Gout is found in 10.3% of RA patients and less than 5% of controls, that being highly significant. Moreover, over time, the risk of gout has gone up in RA patients, and RA seems to be an independent risk factor for gout with an odds ratio of 2.67, strongest for seronegative RA.
I got to say there's still some confusion here. Seronegative RA — could that not be gout? How do they know it was RA? RA is stable over time, but the risk of gout in RA is increasing and trending over time. Well, isn't the odds of gout increasing over time in association with the obesity epidemic? Yeah, there's still some cloudiness here. Yes, if you're an expert rheumatologist, you can diagnose both. Although I do like the idea of letting the labs make up part of the decision, or letting imaging make up part of the decision, or ultrasound, if you will — because they're kind of different, are they not, by those parameters.
Nonetheless, I do think that it's worth considering that diagnosis. What else can you do in gout patients? This is a meta-analysis of eight studies, 2,600 gout patients, showing that predictors of future acute gout attacks would be — and you know what, they didn't put uric acid in this paper, I don't know why — but they did go on and on and on about an elevated neutrophil-to-lymphocyte ratio, NLR, and the same for the platelet-to-lymphocyte ratio, the PLR. The NLR number should be like greater than four. I don't know what the PLR cutoff is, but if those numbers are high, your patients are probably at higher risk for a gout attack coming up soon.
We're going to end with a whole lot of lupus studies and then open access. So, the prevalence of lupus in Australia — what do you think it is? United States, I know what the Lupus Foundation says: it's 5 million, 95 million. They're equating ANA positivity with lupus. That's wrong. You know, most of the epidemiologic studies in the United States say it's somewhere between 219,000 and 299,000 in the United States who have lupus.
In Australia, which has one — what is that, one-thirteenth the population of the United States — the prevalence of lupus is 26,788: 16,000 certain, 10,000 less certain. So the incidence between 2010 and 2022 went from 77 to 127 per 100,000, and that's looking at certain diagnoses. About half of the patients with lupus in Australia are being managed in an outpatient setting. These numbers, by the way, are on par with the same kind of incidence rates in the United States.
Arthritis Care and Research had an important study this week about cause of death in lupus. It's a CDC study that looked at death certificates over a 5-year period where they found almost 15,000 SLE deaths. About 43% of the death certificates listed lupus as the primary cause of death. When you look at the mortality rate per million, it was about six times higher in females than males — almost 6 versus 1.1 in females versus 1.1 in males. It's over 10 — 10.7 per million in African Americans.
What are the causes of death? Heart disease was double the rate of cancer and double the rate of COVID, and all of this occurred during the COVID era, so that's why they're using that as a reference point. A lot of lupus patients must have died from COVID.
Hydroxychloroquine — a report from British Columbia showing that adherence to hydroxychloroquine in either RA or lupus was associated with a significantly lower risk of hospitalization. Again, you might have remembered I wrote an article within the last four months about how everybody with RA should be on hydroxychloroquine as part of a combination, because it has the same benefits in RA that it does in lupus — where we know it lowers glucose and insulin resistance, and it lowers lipids, and it lowers cardiovascular events, and so on, and is better for pregnancy outcomes. Again, the same thing holds true, I think, in RA. And here's more evidence of that.
Other lupus news: the FDA this week granted fast-track designation to Johnson and Johnson's FcRn drug — the neonatal Fc receptor blockade called nipocalimab. As you know, that's been studied in Sjögren's and has been studied in RA. Looked good in Sjögren's in phase 2, not so plus-plus-minus in RA. It's a positive phase 2. The phase 2 JASMINE study looked good, and now it's in
a phase three trial in lupus. So again, it's fast-tracked for its use in lupus. It'll be interesting to see how that comes out.
We also had a nice review article written by Dr. Irvy Zala. Dr. Zala is a resident at Northwestern who wrote a nice review of calcineurin inhibitors in lupus nephritis. Most of us don't use calcineurin inhibitors yet. There's three out there. There's cyclosporin — Arie Kavanagh and I and Peter Lipsky were using that back in our lupus clinic at Parkland back in the late 80s in our difficult cases. Tacrolimus is out there and more recently FDA approved is voclosporin. As you know, the lupus nephritis guidelines talk about the use of calcineurin inhibitors. If you have stage three or four disease, they want you to be on triple therapy that includes steroids, mycophenolate, and either belimumab or a calcineurin inhibitor. But if you have pure stage five, the lupus guidelines say that you should get steroids, mycophenolate, and a calcineurin inhibitor, but not if the eGFR is less than 45 per minute. Meaning if they're CKD 3B or worse, you probably don't want to use it because of the chance of nephrotoxicity. So again, these are important adjuncts that we should be using. As you know, the package insert says that the indication for use of the lone calcineurin inhibitor FDA approved — voclosporin — is in the treatment of adults with lupus nephritis as part of a regimen that involves an immunosuppressant.
And lastly, I got a few more things. Open access arthrology clinics. This was a great report coming out of Denmark, and in this study — where are my — where's my data — a single center retrospective study of a 5-year experience, and what they were trying to do was facilitate referrals of arthralgia patients from primary care to rheumatologists or to the early arthritis clinic. They've inserted this in between the primary care and the early arthritis clinic to make these fast-track 10-minute evaluations done by experienced rheumatologists. Over a 5-year period, they did 761 open access arthralgia clinic evaluations. And again, they just get referred with or without labs, with or without imaging. In this 5 years, 20% of the patients were referred directly to the early arthritis clinic and 80% were discharged. Of the ones that went to the early arthritis clinic, 11% had inflammatory arthritis and half of them had RA. A total of 32 new onset RA patients were diagnosed, with one in five — or 20% — of them coming from the open access arthrology clinic.
Why do I like this? I did this as a screening tool to get patients into a study. I was trying to recruit for OA of the knee for an NIH study — the glucosamine GAIT study. And we did these basically open access arthralgia clinics. We advertised it in the paper as free arthritis clinic evaluations. No diagnoses or prescriptions would be provided, meaning they're going to get a fast evaluation. And we saw — I think we did six of these — we saw like 60 people every afternoon and they got about a five-minute evaluation, and we saw the same kind of results. Except I was able to recruit like 80 or 90 people for my OA study, but we had a bunch of people that got referred to our early arthritis clinic or to our regular rheumatology clinic, and then we referred people to other areas for other things.
The point being: why aren't we doing this in practice? When I was teaching about the advantages of doing an early arthritis clinic, I had lots of positive responses, but nobody did it because it really means that you would have to open up a slot and leave a slot empty for Wednesday afternoon that your primary care people could refer to. Maybe two slots during the week, two hours each. My point was leave them open and then you're going to fill them, because there's always people calling for appointments, and if you don't fill them then you're going to see someone with fibromyalgia earlier than 6 months. But if it's a new early RA referral, great; if it's a new onset arthralgia, even better. And by the way, these are fast evaluations. You're great at pattern recognition. I think everybody should be doing this. Congratulations to the Danish investigators who did this.
A few more things. One, if you have dermatology colleagues, make sure you refer them to the Derm on RheumNow podcast. I do that monthly. You can see it on the website, you can see it on YouTube, it's on our podcast channels. It's basically a compilation of all the dermatology content for the dermatologist that I have already shared with you, because you're a rheumatologist or you're rheum-interested.
Another thing — RheumNow Live is done. But if you missed it, now's the time to get it. Even still, you can now get RheumNow Live on demand by going to RheumNow.live. It's 2 days of the best and most recent clinical updates with the best faculty. You can
download all the materials. You can view all the slides. All the sessions. You can listen to them or watch them. You can do it whenever you want. There are pre-learn downloads. There are actual lecture downloads. Again, all of it can be accessed either in the show notes or by going to RheumNow.live.
One more. I've been holding this one back for a few weeks because we were so busy, but I want to get to it today. This is coming from Ask Cush — anything from the website. You can go to the website, lower right-hand corner, click on there and dictate or record your case and I'll discuss it here on the podcast.
This one comes from Gita Fathi. Gita is a rheumatologist in Camaro, California, and she sent me a case that she knew I couldn't resist. It's about Still's disease. A 42-year-old thin woman diagnosed with Still's disease — it looks like 20 years ago. Onset of rash — didn't say what kind — sore throat, arthritis, fevers up to 103, hepatosplenomegaly, lymphadenopathy. We see a prodromal sore throat, seronegative for RF and ANA, ferritin at times greater than 40,000, and evidence of transaminitis. You'd say, well, it sounds like Still's disease.
Well, when she plugged it in, I said, well, go back and plug it into StillsNow.com, put it in the Still's calculator. She said it didn't meet the Cush criteria for Still's disease, but it did meet the Yamaguchi criteria. And we all know that the Yamaguchi criteria are very good. And you can imagine what I might say about the Cush criteria.
But nonetheless, this patient had by my criteria eight points — you need 10 points. If the patient had the classic rash, the evanescent salmon-pink rash, then she'd be at nine points. If she had the quotidian fever that was classic, she'd have, again, maybe 10 points. If the arthritis was more than one joint and it was a polyarthritis, it might have met Cush criteria. But that's not why she's writing me. She's writing me because the patient is difficult to treat — meaning that in spite of being treated with anakinra, Actemra, anakinra in double dose, Actemra in high doses, canakinumab, methotrexate, infliximab, and even a JAK inhibitor, tofacitinib — she cannot get the patient's steroids below 20 milligrams a day. And that was the question.
So more recently the patient has only been able to get down to like 25, sometimes 20 milligrams of prednisone a day while on methotrexate 15 a week plus canakinumab 300 every other week. And again, they tried replacing the methotrexate with tofacitinib at 10 once a day or 10 twice a day — still unable to wean the steroids.
Anyway, my answer back to Gita was: number one, does it meet the criteria? Number two, when you encounter what you think is difficult-to-treat Still's disease, my first go-to is to call someone who treats a lot of Still's disease. And by the way, that includes the pediatric rheumatologists, who are way better at this than we adults, because they see it all the time. And pediatric Still's is the same disease as adult Still's. Or call a rheumatologist in your community that you know sees a lot of Still's. Or if you don't know, call me or send me an email like Gita did, and I'll always respond back to you or present it here on the podcast.
But when you get difficult-to-treat Still's disease and they're really not behaving as they should when you use your strongest drugs, then the first thing I do is genetic testing — meaning I'm going to send off a panel of genes that look for autoinflammatory conditions.
So I said to Gita: in my clinic I've seen hundreds of referrals from rheumatologists from all over the country, all over the world. And of all the referrals I've ever gotten — and these coming from very smart, great rheumatologists like yourself — only 40% have Still's disease by criteria, by my criteria or Yamaguchi. I don't feel bad about that, because if I were working with Raphaela Goldbach-Mansky and Dan Kastner in their autoinflammatory clinic at the NIH, we would know that only 60% of their autoinflammatory patients have a defined diagnosis, and there's 40% that we're just not going to know — but we're going to manage them.
So, get a gene panel. Maybe you get another insight as to what this could be. And the algorithm here begins with: are you treating systemic disease, or are you treating arthritis? If you're treating arthritis with Still's, then treat it as if it's RA. Are you treating systemic disease — and by that I mean high fevers, evanescent rashes, serositis, high white cell counts, very high sed rates and CRP? I don't hang my hat on ferritin. Only 50% of patients have an elevated ferritin, and only 10% have that hyperferritinemia that you all think is so pathognomonic when it really isn't. But it's great if I see hyperferritinemia — I'm worried about MAS. And yes, Still's is a cause of MAS.
So, are you treating systemic disease? And if you do, European and PRINTO guidelines and ACR guidelines say use an
IL-1 inhibitor or IL-6 inhibitor first. And that steroids, you know, aren't the first line therapy.
Okay. And in my experience again it's IL-1 or IL-6 often in high doses right — maybe higher than what you're prepared to use — not 100 once a day of anakinra but maybe 100 twice a day or 200 QHS, because IL-1 is secreted at night when they're asleep.
Same thing with IL-6, the TENDER trial. Use doses, and this is in kids with systemic JIA, use doses up to 12 milligrams per kilogram, and you're playing around with four or maybe eight. Again, I wouldn't want to be on 12 for a long period of time, but at least to get control of disease.
And then I like using JAK inhibitors, but we need to see clinical trials of JAK inhibitors. My experience has been positive, and everybody's probably on a background of methotrexate if they have problematic disease.
I wrote down — I don't think there's any value in trying for systemic disease — trying abatacept, cyclosporine, or even more steroids. For me, the jury's out about adjunctive use of azathioprine, hydroxychloroquine, or a calcineurin inhibitor.
Anyway, you got a case, go to the website, bottom left-hand corner, click on Ask Cush Anything and we'll discuss your case in the future here on the podcast. Oh, we've arrived at your destination. The bill is as shown on the meter. Take care.
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