Infectious Rheumatology (5.15.2026) Save
Transcription
Hi everyone, this is the RheumNow podcast for May the 15, 2026. I'm Jack Cush with RheumNow. Before we get into the podcast, I want to remind you about a series of videos that are on the website. They're called Advanced Practice Rheum. These are designed to be short mini lectures, 10 to 15 minutes on topics. And I did these really for people who are just starting out in rheumatology. And I think you should refer your residents, your students, your fellows, new hires, physician assistants and nurse practitioners who are starting out with you to check these out. Again, there'll be about 13 or 14 of them. The ones that are up there right now include these mini lectures, again up to about 15 minutes, on evaluation of musculoskeletal complaints, evaluation by laboratory tests including rheumatoid factor, CCP, and another one on acute phase reactants, sed rate, CRP. I have lectures on lupus, fibromyalgia, difficult to treat RA, Still's disease, and glucocorticoids, and soon to follow is going to be spondyloarthropathies and psoriatic arthritis. So they're there for the people that you want to get up to speed on topics in rheumatology and the evaluation and care of the patients that we take care of.
This week on the podcast, a lot of interesting reports. There was a letter to the New England Journal about a week or two weeks ago where someone reported on their 10-year study of 147 patients undergoing partial meniscectomies by arthroscopy. And you know this is a sort of standard of care where they fashion the damaged meniscus by arthroscopic repair of it, leaving some in place, and they do these for degenerative tears. In this specific study, 147 patients who did not have a coexistent knee OA were either treated with partial meniscectomies or with sham surgery, and they looked at 10-year outcomes and showed no benefit to the meniscus surgery over sham surgery. In fact, they may have in fact done worse. And there is some literature out there, especially in people who have OA, that if you do meniscal surgery or you try to clean things up in the knee with the meniscus and such structures, you may worsen the OA. So that's why there has been this move over the last 10 years to manage those conservatively and not take them to surgery.
A number of good reports this week relating to rheumatology but being infectious in nature. JAMA Insights presented a review of chikungunya, basically saying that it's a worldwide disorder affecting 35 million people, and it's mainly in the tropics and subtropics. It can be in the Caribbean. The people who are affected here are those who live there or people who travel there. As you know, this is a mosquito-borne alphavirus. And I've seen a number of cases in the last several years since we started reporting this. They do have fever. They do get arthritis and polyarthritis. Less so do they have rashes, myalgias, nausea, vomiting, constitutional things, conjunctivitis, rarely myocarditis. But I like these reports because I think I like saying the word chikungunya. It sounds to me like an entrée item on a fusion restaurant that I might have visited in Jamaica. But actually the word chikungunya comes from the local language in Tanzania and Mozambique, where the word means to bend up or to become contorted. Yes, I did look this up, and what they're describing really is the bent-over posture of those who are suffering with severe joint pain and arthralgia. So the word chikungunya comes from the musculoskeletal manifestations of chikungunya. That's rheumatology trivia, advanced trivia that you now know.
JAMA Dermatology did a case of parvovirus B19 affecting an adult. That was kind of cool. A 40-year-old, two days of asymptomatic red rash on the cheeks but also in the inguinal region, flanks, axilla, fever 39, arthralgias. The white count was 2,000, the rest of the CBC was normal, the sed rate was normal, the CRP was really elevated, 124 milligrams per liter. And it was diagnosed by PCR to identify the parvovirus. Again, as we get older we are all going to be exposed to parvovirus and we may not get the infection. The vast majority of us won't. And by the time you get above 60, the majority of the population has IgG antibodies to parvovirus and should be protected. The group that's probably least protected serologically, meaning they've not had exposure, are in fact women in their childbearing years, which is why this is an issue when women get infected — that they could pass this on to the child. So the point here is this does happen in adults, and serologics are not useful. You need to do PCR to make the diagnosis. When it happens, symptomatic management, although I've had — I think I've had like two or three
patients that started out with proven parvovirus B19 that ended up with a chronic arthropathy that I then had to at some point, you know, flip the switch and stop calling it parvovirus B19 polyarthritis and start calling it seronegative RA — that happens too.
One of the most common complications in clinical trials in RA trials that I've done and others: the most common adverse event that gets reported is non-serious infectious events — NSIE. I've written about that in the past with Katherine Dao, Will Dixon, and the BSR has written about that. This is the most common thing; it may occur in 30 to 60% of patients. But the question always is: do our drugs — advanced drugs, especially biologics, targeted synthetics — do they cause more NSIEs? And the answer has always been no. And this is far, far, far more common than the serious infectious events, which are hospitalizable, needing IV antibiotics, etc.
A patient survey study coming from the Arthritis Power registry — it's now also called the PatientSpot registry — looked at 351 patients who were doing periodic surveys. Against these 350 patients, they had 439 non-serious infectious events. The important thing here is that the thing that was associated with these events was steroids at 10 milligrams per day or greater, but biologics and JAKs had no greater risk compared to patients who are just taking conventional DMARDs.
So, again, that may have some teaching value for you or not, but the real thing is what you're probably not doing. Still, way too many of you are stopping biologics or halting and delaying infusions in people who have the sniffles. You know, it's a non-serious infectious event. They're not going to get hospitalized. They usually don't have any fever. You know, I've always treated them on and told them, "Don't stop. Don't stop until I tell you to stop." Because once they stop, they don't know when to go back on, and then they flare and they get worse. And the main driver of infection — non-serious and serious — is going to be disease not under control. So I say don't hold the infusion; hold the infusion only unless the patient's got a serious high fever or gets hospitalized. Otherwise, power through. It is the right thing to do. And there are many sources that say that, not just me.
We've talked a lot in the past about the risk of TB and mycobacterial infections, and many of you worry about what can I do when the patient's got a history of TB or a positive QuantiFERON-TB test. Again, the linkage between biologics and mycobacterial and TB is with TNF — TNF, TNF, TNF — and maybe a little bit of gamma interferon. If you inhibit TNF, or maybe gamma interferon, that puts the patient at risk for getting a mycobacterial infection and/or for spread of mycobacterial. So again, if TB is in the story and mycobacteria is in the story, give them a non-TNF drug — IL-6, abatacept, B cell inhibitors, even JAKs — although you could say JAKs may have some effect on gamma interferon; their rates are not any higher than what was seen with IL-6 or abatacept. And so again, the risk of reactivation with those non-TNF biologic targeted synthetics is at least a log 10 or 100-fold less than with TNF inhibitors. Don't use a TNF inhibitor if that's what you're worried about.
Anyway, I bring all this up because a retrospective report of almost 1,500 patients with non-tuberculous mycobacterial infections — NTM; used to call this atypical mycobacterium — M. abscessus, M. kansasii, M. avium, all those bugs. First off, those bugs are far more common than TB, and they're usually not as morbid or mortal as far as risk. But in this study of 1,420 NTM patients, 66 had RA — 4.6%. The combination of RA and NTM was a predictor for respiratory-related deaths, meaning RA patients with NTM had almost a four-fold higher risk of dying. So it's not a good combo, but it was a good opportunity to talk about mycobacterial infections in RA and inflammatory arthritis.
Another RA abstract comes from CORRONA Evitas — which used to be called CORRONA. CORRONA Evitas has a registry of, you know, tons of patients. They did an analysis of RA patients starting either on a biologic or targeted synthetic but who also had renal insufficiency — they were CKD, what's that, stage four, with an eGFR of less than 60 cc's per minute. So they found amongst 9,600 patients, 52,000 years of follow-up, that 10% had this degree of renal insufficiency. The point of this was those RA patients don't do well. RA patients with comorbidity — we know they don't do well — but here specifically, RA patients with renal insufficiency were less likely to achieve clinical remission and low disease activity state. So if they didn't have renal insufficiency, 28% were in remission, but if they did, it was only 19% — that's a 24% reduction, and that was significant. So the effectiveness of biologics and targeted synthetics can be curtailed, hampered, by the presence of chronic kidney disease.
right. Um, the Society of Interventional Radiology, who's a card-carrying member of that, issued a position statement this past week about the appropriateness of genicular artery embolization, GAE, in symptomatic OA patients. We've written about that before. There have been a number of reports in JAMA about that. We in rheumatology have never used it, but it works. It works really well. And their position statement says it should be considered in people who have failed conservative therapy and especially if they're not candidates for knee replacement. I think we should be doing more of that.
And by the way, I don't know if you've seen what I've seen, but there's a lot of reports out there about the use of — or people touting the value of — radiation therapy for knee OA. That's a special kind of stupid. That's people just trying to get some business. The evidence for that is weak, weak, weak. I would not do that to any of my patients, and shame on those people who think it's an appropriate intervention. This, on the other hand, done by interventional radiology, has in every study I've reported and found been a positive result and should be considered.
PNAS, Proceedings of the National Academy of Sciences, you know, a very prestigious journal, published a report this week about PTPN22, PTPN22. I know that that gene is associated with RA risk. It doubles the RA risk. It's one of the few genetic associations that strongly is linked to RA that's not an HLA gene, right? And we know that this gene is also associated with risk of other autoimmune disease. This gene, PTPN22, is found in up to 5 to 15% of people in the United States. But in autoimmune disease it's found more than double the rate in RA. I think the number is, you know, above 30% for instance. And it is involved in RA in many of the immunologic abnormalities. For instance, the gene is important in augmenting citrullination, that then leads to risk and or to worse disease in the form of CCP antibodies.
Anyway, this gene not only augments citrullination, it augments innate immunity, enhances NK cell activity, but while these are bad things, the PNAS article said it protected people against coronavirus infection. It's sort of like, you know, these gain-of-function mutations that sometimes have really bad things happen to them but conversely might have some good things happen. This is one such example. There is a positive side to one particular allele of the PTPN22 — that's the 1858C allele — but anyway I thought that was interesting enough to bring to your attention.
A registry study — was it coming out of the NIH? I think it was — looked at, let me think about that — no, that's another study on mortality from the NIH. This was a registry study that looked at 587 patients with lupus and examined the importance of RNP antibodies. Now, I would have thought, you know, RNP antibodies, who cares? It's sort of like one of the antibodies that is almost always found in people who have a speckled pattern ANA, which is almost always found in anyone with a positive ANA. So when you order RNP, you get RNP and Sm together, do you not?
Well, they found that 30% of their 587 patients were RNP positive, and they showed compared to RNP negative people that RNP positives had more disease activity, had higher SLEDAI scores — eight versus four — and more use of drugs including glucocorticoids, 7 milligrams a day versus 3 milligrams a day. RNP positive patients had more renal disease, skin disease, serologic activity, and were less likely to achieve LLDAS — 20% versus 32% — or remission, 12% versus 23%.
More importantly — or less, I don't know, co-associated here — is that if they were RNP positive they had an 18-fold higher likelihood of being Sm positive. Sm we know is more specific for lupus and also more prognostic for more severe disease. So the benign nature of RNP was sort of busted in my brain by this report, and this is why I do note it, or do test for it, and do note it in the chart of people who I do serologics in.
I'm going to get to another lupus report later, but there was a report about renal crisis in scleroderma and pulmonary artery hypertension, basically showing amongst 234 patients with scleroderma that 7% had both pulmonary hypertension and renal crisis, and that — surprisingly to me — the pulmonary hypertension can precede the renal crisis, but it can also come on at the same time. So there is no clear sequence of development here.
And you know, I don't usually — I'm not usually looking that hard for pulmonary artery hypertension usually in people with limited disease, CREST disease, and usually over a long period of time, but you know it does happen in diffuse disease as well, which is where you see more renal crisis cases, do you not? Nonetheless, people with systemic sclerosis who have both pulmonary hypertension and sclerodermal renal crisis — as if that isn't
enough, have almost a tenfold risk of GI bleeds. Oh my goodness. Really? So again, never good news for scleroderma, but these are the — you can identify these people by these occurrences, by these features. Again, those two occurrences are also more likely with age and people who are more likely to have elevated anti-proBNP, you know, often associated with heart and/or lung disease, I guess.
Uh, found a report this week about an inverse relationship between femoral bone mineral density and osteoporosis levels of depressed BMDs and all-cause mortality. This has been reported before that osteoporosis is a risk factor for all-cause mortality. In this report of almost 3,000 post-menopausal women — this is from NHANES done over a 13-year period — there was a 47% increase in mortality, hazard ratio 1.47. Why do they die? Why does osteoporosis lead to increased mortality? Two reasons. One, fracture-related mortalities, which are real especially in the elderly and are more of a problem with hip fractures than other fractures related to osteoporosis. And then osteoporosis itself is a sign of frailty, and frailty being a risk factor for mortal if not morbid outcomes. Kind of interesting.
Um, I'm not familiar — maybe you are — with ANCA-associated pachymeningitis. The report that I put up says it's rare. The report was about 230 patients with systemic vasculitis from 170 reports. 108 of those were MPO positive. 71 were PR3 positive. ANCA-associated pachymeningitis has been more reported in the literature with GPA than other forms like MPA and other forms of ANCA-associated vasculitis. They usually present with headaches, cranial neuropathy, and acute phase reactants. The cranial neuropathies can present with visual issues, diplopia, vision loss, hearing problems, ocular palsies, etc. These people all had other systemic features, usually ENT, lungs, kidney, orbits. The acute phase reactants are abnormal and high. The CSF is abnormal. Again, it is a rare manifestation of ANCA-associated vasculitis, probably less than 5% of cases. And the diagnosis is made by thickening of the meninges and these abnormal tests, but this pachymeningitis picture — you shouldn't automatically assume it is due to the ANCA-associated vasculitis GPA or MPA, because the differential diagnosis includes other infections and cancers and RA and other rheumatic diseases, sarcoidosis, and IgG4-related disease. ANCA-associated pachymeningitis kind of gives you a clue that they may have the vasculitis.
Osteoporosis International had an interesting paper from Buenos Aires — Dr. Osvaldo Messina, a good friend, brought this to my attention. It was a systematic review of vitamin D deficiency looking at many sources to find out what's the deal with vitamin D deficiencies and rheumatic diseases. We certainly know that vitamin D deficiency is very high in patients with autoimmune and rheumatic disease. The paper that looked at association says it was associated with higher disease activity, with fatigue, and poorer musculoskeletal outcomes. They did say that there's ample evidence that supplementation works. They also did not show that supplementation — while it may work in increasing vitamin D levels — doesn't fix anything that you can measure; that when it comes to large trials and Mendelian randomization studies, vitamin D doesn't cause disease and isn't associated with sustained remission, meaning that when you treat it doesn't make people better.
Do I recommend it? Yes. Do I take it myself? Yes. It's good for bone health. It's good for B cells and immune function. It's very important probably for lupus patients. But the problem is the research is crappy. A lot of heterogeneity. A lot of non-standard study designs. Rheumatologists just love vitamin D and I just love to make fun of it. Fault me if you will, but just test it, treat it, and don't think you're treating their fatigue. I don't believe that fatigue gets better or disease activity gets better. Although Michelle Petri's got some data about lupus patients doing better on supplementation. So, you know, maybe I'll back off on that a little bit.
Uh, this study was published in ACR Open Rheumatology — anyway, this particular study that appeared in MedPage Today, which is coming from the original journal article, found that lupus in young women leads to death. So lupus patients die. Yes, we know that. And it's less and less as time has gone on, but to my surprise — and it really shouldn't be — a lot of it happens during the childbearing years in lupus patients. So when they looked at years of life lost, lupus was the cause, and it was 14th as a cause in women between the ages of
15 and 44. It was ninth between the ages of 15 and 25 amongst the autoimmune diseases. It was either the first or second greatest cause for years of life lost. It was behind other causes of death in these women and that would include diabetes, HIV, lung disease, anemia, cardiovascular and cerebrovascular disease and nephritis. But it still is, you know, lupus can be deadly and we know that. And uh but luckily we're getting more therapies. We're being more aggressive. We're limiting our use of steroids. I like the way lupus is going.
Another report, the final report for this podcast, was about drugs that target toll-like receptors. There are usually drugs out there targeting TLR7. This one — enpatoran — enpatoran is a small molecule inhibitor of TLR7 and TLR8, and was reported in the Willow study, a phase 2 trial of 463 patients with cutaneous lupus erythematosus, CLLE, or systemic patients who did not have extracutaneous disease, and they looked at whether this drug would affect the skin outcomes and measured that by a CLASI outcome score at week 16. So they either got placebo or the TLR7/8 inhibitor, and they showed that it was highly effective, with 50 to 70% better responses compared to the placebo.
So again this is important because toll-like receptor activation is very much involved in the innate immune response, which is important in the handling of viruses but also in the genesis of adaptive immune responses and autoimmune disease. There are mutations of TLR7 that have been linked to excessive activity that then leads to childhood lupus. So these therapies, which have been reported at the last few ACR and EULAR meetings, are getting closer to the market and I think that they'll be an add-on. And of course some people believe that hydroxychloroquine — one of its many effects, most of which are unknown and truly unclear, but we know it's good enough that we give everyone with lupus hydroxychloroquine because it's so safe — that maybe its mechanism of action is through inhibition of TLR7 or, I think, not nine.
So what about the safety of the TLR inhibitors? Looks really good. Nothing there that looks scary at all, and nothing learned from knockout models or mutation models for the toll-like receptors. So maybe it will compete with hydroxychloroquine for safety as well as efficacy.
Anyway, that's it for a long edition of this podcast. We're going to do it again next week. I want you to know we're getting ready to cover EULAR, which is about two weeks or two and a half weeks away. We'll be there. Hope you'll be following us. Hope you are going to enjoy that as much as you have in the past. Take care of yourselves. We'll talk next week.
This week on the podcast, a lot of interesting reports. There was a letter to the New England Journal about a week or two weeks ago where someone reported on their 10-year study of 147 patients undergoing partial meniscectomies by arthroscopy. And you know this is a sort of standard of care where they fashion the damaged meniscus by arthroscopic repair of it, leaving some in place, and they do these for degenerative tears. In this specific study, 147 patients who did not have a coexistent knee OA were either treated with partial meniscectomies or with sham surgery, and they looked at 10-year outcomes and showed no benefit to the meniscus surgery over sham surgery. In fact, they may have in fact done worse. And there is some literature out there, especially in people who have OA, that if you do meniscal surgery or you try to clean things up in the knee with the meniscus and such structures, you may worsen the OA. So that's why there has been this move over the last 10 years to manage those conservatively and not take them to surgery.
A number of good reports this week relating to rheumatology but being infectious in nature. JAMA Insights presented a review of chikungunya, basically saying that it's a worldwide disorder affecting 35 million people, and it's mainly in the tropics and subtropics. It can be in the Caribbean. The people who are affected here are those who live there or people who travel there. As you know, this is a mosquito-borne alphavirus. And I've seen a number of cases in the last several years since we started reporting this. They do have fever. They do get arthritis and polyarthritis. Less so do they have rashes, myalgias, nausea, vomiting, constitutional things, conjunctivitis, rarely myocarditis. But I like these reports because I think I like saying the word chikungunya. It sounds to me like an entrée item on a fusion restaurant that I might have visited in Jamaica. But actually the word chikungunya comes from the local language in Tanzania and Mozambique, where the word means to bend up or to become contorted. Yes, I did look this up, and what they're describing really is the bent-over posture of those who are suffering with severe joint pain and arthralgia. So the word chikungunya comes from the musculoskeletal manifestations of chikungunya. That's rheumatology trivia, advanced trivia that you now know.
JAMA Dermatology did a case of parvovirus B19 affecting an adult. That was kind of cool. A 40-year-old, two days of asymptomatic red rash on the cheeks but also in the inguinal region, flanks, axilla, fever 39, arthralgias. The white count was 2,000, the rest of the CBC was normal, the sed rate was normal, the CRP was really elevated, 124 milligrams per liter. And it was diagnosed by PCR to identify the parvovirus. Again, as we get older we are all going to be exposed to parvovirus and we may not get the infection. The vast majority of us won't. And by the time you get above 60, the majority of the population has IgG antibodies to parvovirus and should be protected. The group that's probably least protected serologically, meaning they've not had exposure, are in fact women in their childbearing years, which is why this is an issue when women get infected — that they could pass this on to the child. So the point here is this does happen in adults, and serologics are not useful. You need to do PCR to make the diagnosis. When it happens, symptomatic management, although I've had — I think I've had like two or three
patients that started out with proven parvovirus B19 that ended up with a chronic arthropathy that I then had to at some point, you know, flip the switch and stop calling it parvovirus B19 polyarthritis and start calling it seronegative RA — that happens too.
One of the most common complications in clinical trials in RA trials that I've done and others: the most common adverse event that gets reported is non-serious infectious events — NSIE. I've written about that in the past with Katherine Dao, Will Dixon, and the BSR has written about that. This is the most common thing; it may occur in 30 to 60% of patients. But the question always is: do our drugs — advanced drugs, especially biologics, targeted synthetics — do they cause more NSIEs? And the answer has always been no. And this is far, far, far more common than the serious infectious events, which are hospitalizable, needing IV antibiotics, etc.
A patient survey study coming from the Arthritis Power registry — it's now also called the PatientSpot registry — looked at 351 patients who were doing periodic surveys. Against these 350 patients, they had 439 non-serious infectious events. The important thing here is that the thing that was associated with these events was steroids at 10 milligrams per day or greater, but biologics and JAKs had no greater risk compared to patients who are just taking conventional DMARDs.
So, again, that may have some teaching value for you or not, but the real thing is what you're probably not doing. Still, way too many of you are stopping biologics or halting and delaying infusions in people who have the sniffles. You know, it's a non-serious infectious event. They're not going to get hospitalized. They usually don't have any fever. You know, I've always treated them on and told them, "Don't stop. Don't stop until I tell you to stop." Because once they stop, they don't know when to go back on, and then they flare and they get worse. And the main driver of infection — non-serious and serious — is going to be disease not under control. So I say don't hold the infusion; hold the infusion only unless the patient's got a serious high fever or gets hospitalized. Otherwise, power through. It is the right thing to do. And there are many sources that say that, not just me.
We've talked a lot in the past about the risk of TB and mycobacterial infections, and many of you worry about what can I do when the patient's got a history of TB or a positive QuantiFERON-TB test. Again, the linkage between biologics and mycobacterial and TB is with TNF — TNF, TNF, TNF — and maybe a little bit of gamma interferon. If you inhibit TNF, or maybe gamma interferon, that puts the patient at risk for getting a mycobacterial infection and/or for spread of mycobacterial. So again, if TB is in the story and mycobacteria is in the story, give them a non-TNF drug — IL-6, abatacept, B cell inhibitors, even JAKs — although you could say JAKs may have some effect on gamma interferon; their rates are not any higher than what was seen with IL-6 or abatacept. And so again, the risk of reactivation with those non-TNF biologic targeted synthetics is at least a log 10 or 100-fold less than with TNF inhibitors. Don't use a TNF inhibitor if that's what you're worried about.
Anyway, I bring all this up because a retrospective report of almost 1,500 patients with non-tuberculous mycobacterial infections — NTM; used to call this atypical mycobacterium — M. abscessus, M. kansasii, M. avium, all those bugs. First off, those bugs are far more common than TB, and they're usually not as morbid or mortal as far as risk. But in this study of 1,420 NTM patients, 66 had RA — 4.6%. The combination of RA and NTM was a predictor for respiratory-related deaths, meaning RA patients with NTM had almost a four-fold higher risk of dying. So it's not a good combo, but it was a good opportunity to talk about mycobacterial infections in RA and inflammatory arthritis.
Another RA abstract comes from CORRONA Evitas — which used to be called CORRONA. CORRONA Evitas has a registry of, you know, tons of patients. They did an analysis of RA patients starting either on a biologic or targeted synthetic but who also had renal insufficiency — they were CKD, what's that, stage four, with an eGFR of less than 60 cc's per minute. So they found amongst 9,600 patients, 52,000 years of follow-up, that 10% had this degree of renal insufficiency. The point of this was those RA patients don't do well. RA patients with comorbidity — we know they don't do well — but here specifically, RA patients with renal insufficiency were less likely to achieve clinical remission and low disease activity state. So if they didn't have renal insufficiency, 28% were in remission, but if they did, it was only 19% — that's a 24% reduction, and that was significant. So the effectiveness of biologics and targeted synthetics can be curtailed, hampered, by the presence of chronic kidney disease.
right. Um, the Society of Interventional Radiology, who's a card-carrying member of that, issued a position statement this past week about the appropriateness of genicular artery embolization, GAE, in symptomatic OA patients. We've written about that before. There have been a number of reports in JAMA about that. We in rheumatology have never used it, but it works. It works really well. And their position statement says it should be considered in people who have failed conservative therapy and especially if they're not candidates for knee replacement. I think we should be doing more of that.
And by the way, I don't know if you've seen what I've seen, but there's a lot of reports out there about the use of — or people touting the value of — radiation therapy for knee OA. That's a special kind of stupid. That's people just trying to get some business. The evidence for that is weak, weak, weak. I would not do that to any of my patients, and shame on those people who think it's an appropriate intervention. This, on the other hand, done by interventional radiology, has in every study I've reported and found been a positive result and should be considered.
PNAS, Proceedings of the National Academy of Sciences, you know, a very prestigious journal, published a report this week about PTPN22, PTPN22. I know that that gene is associated with RA risk. It doubles the RA risk. It's one of the few genetic associations that strongly is linked to RA that's not an HLA gene, right? And we know that this gene is also associated with risk of other autoimmune disease. This gene, PTPN22, is found in up to 5 to 15% of people in the United States. But in autoimmune disease it's found more than double the rate in RA. I think the number is, you know, above 30% for instance. And it is involved in RA in many of the immunologic abnormalities. For instance, the gene is important in augmenting citrullination, that then leads to risk and or to worse disease in the form of CCP antibodies.
Anyway, this gene not only augments citrullination, it augments innate immunity, enhances NK cell activity, but while these are bad things, the PNAS article said it protected people against coronavirus infection. It's sort of like, you know, these gain-of-function mutations that sometimes have really bad things happen to them but conversely might have some good things happen. This is one such example. There is a positive side to one particular allele of the PTPN22 — that's the 1858C allele — but anyway I thought that was interesting enough to bring to your attention.
A registry study — was it coming out of the NIH? I think it was — looked at, let me think about that — no, that's another study on mortality from the NIH. This was a registry study that looked at 587 patients with lupus and examined the importance of RNP antibodies. Now, I would have thought, you know, RNP antibodies, who cares? It's sort of like one of the antibodies that is almost always found in people who have a speckled pattern ANA, which is almost always found in anyone with a positive ANA. So when you order RNP, you get RNP and Sm together, do you not?
Well, they found that 30% of their 587 patients were RNP positive, and they showed compared to RNP negative people that RNP positives had more disease activity, had higher SLEDAI scores — eight versus four — and more use of drugs including glucocorticoids, 7 milligrams a day versus 3 milligrams a day. RNP positive patients had more renal disease, skin disease, serologic activity, and were less likely to achieve LLDAS — 20% versus 32% — or remission, 12% versus 23%.
More importantly — or less, I don't know, co-associated here — is that if they were RNP positive they had an 18-fold higher likelihood of being Sm positive. Sm we know is more specific for lupus and also more prognostic for more severe disease. So the benign nature of RNP was sort of busted in my brain by this report, and this is why I do note it, or do test for it, and do note it in the chart of people who I do serologics in.
I'm going to get to another lupus report later, but there was a report about renal crisis in scleroderma and pulmonary artery hypertension, basically showing amongst 234 patients with scleroderma that 7% had both pulmonary hypertension and renal crisis, and that — surprisingly to me — the pulmonary hypertension can precede the renal crisis, but it can also come on at the same time. So there is no clear sequence of development here.
And you know, I don't usually — I'm not usually looking that hard for pulmonary artery hypertension usually in people with limited disease, CREST disease, and usually over a long period of time, but you know it does happen in diffuse disease as well, which is where you see more renal crisis cases, do you not? Nonetheless, people with systemic sclerosis who have both pulmonary hypertension and sclerodermal renal crisis — as if that isn't
enough, have almost a tenfold risk of GI bleeds. Oh my goodness. Really? So again, never good news for scleroderma, but these are the — you can identify these people by these occurrences, by these features. Again, those two occurrences are also more likely with age and people who are more likely to have elevated anti-proBNP, you know, often associated with heart and/or lung disease, I guess.
Uh, found a report this week about an inverse relationship between femoral bone mineral density and osteoporosis levels of depressed BMDs and all-cause mortality. This has been reported before that osteoporosis is a risk factor for all-cause mortality. In this report of almost 3,000 post-menopausal women — this is from NHANES done over a 13-year period — there was a 47% increase in mortality, hazard ratio 1.47. Why do they die? Why does osteoporosis lead to increased mortality? Two reasons. One, fracture-related mortalities, which are real especially in the elderly and are more of a problem with hip fractures than other fractures related to osteoporosis. And then osteoporosis itself is a sign of frailty, and frailty being a risk factor for mortal if not morbid outcomes. Kind of interesting.
Um, I'm not familiar — maybe you are — with ANCA-associated pachymeningitis. The report that I put up says it's rare. The report was about 230 patients with systemic vasculitis from 170 reports. 108 of those were MPO positive. 71 were PR3 positive. ANCA-associated pachymeningitis has been more reported in the literature with GPA than other forms like MPA and other forms of ANCA-associated vasculitis. They usually present with headaches, cranial neuropathy, and acute phase reactants. The cranial neuropathies can present with visual issues, diplopia, vision loss, hearing problems, ocular palsies, etc. These people all had other systemic features, usually ENT, lungs, kidney, orbits. The acute phase reactants are abnormal and high. The CSF is abnormal. Again, it is a rare manifestation of ANCA-associated vasculitis, probably less than 5% of cases. And the diagnosis is made by thickening of the meninges and these abnormal tests, but this pachymeningitis picture — you shouldn't automatically assume it is due to the ANCA-associated vasculitis GPA or MPA, because the differential diagnosis includes other infections and cancers and RA and other rheumatic diseases, sarcoidosis, and IgG4-related disease. ANCA-associated pachymeningitis kind of gives you a clue that they may have the vasculitis.
Osteoporosis International had an interesting paper from Buenos Aires — Dr. Osvaldo Messina, a good friend, brought this to my attention. It was a systematic review of vitamin D deficiency looking at many sources to find out what's the deal with vitamin D deficiencies and rheumatic diseases. We certainly know that vitamin D deficiency is very high in patients with autoimmune and rheumatic disease. The paper that looked at association says it was associated with higher disease activity, with fatigue, and poorer musculoskeletal outcomes. They did say that there's ample evidence that supplementation works. They also did not show that supplementation — while it may work in increasing vitamin D levels — doesn't fix anything that you can measure; that when it comes to large trials and Mendelian randomization studies, vitamin D doesn't cause disease and isn't associated with sustained remission, meaning that when you treat it doesn't make people better.
Do I recommend it? Yes. Do I take it myself? Yes. It's good for bone health. It's good for B cells and immune function. It's very important probably for lupus patients. But the problem is the research is crappy. A lot of heterogeneity. A lot of non-standard study designs. Rheumatologists just love vitamin D and I just love to make fun of it. Fault me if you will, but just test it, treat it, and don't think you're treating their fatigue. I don't believe that fatigue gets better or disease activity gets better. Although Michelle Petri's got some data about lupus patients doing better on supplementation. So, you know, maybe I'll back off on that a little bit.
Uh, this study was published in ACR Open Rheumatology — anyway, this particular study that appeared in MedPage Today, which is coming from the original journal article, found that lupus in young women leads to death. So lupus patients die. Yes, we know that. And it's less and less as time has gone on, but to my surprise — and it really shouldn't be — a lot of it happens during the childbearing years in lupus patients. So when they looked at years of life lost, lupus was the cause, and it was 14th as a cause in women between the ages of
15 and 44. It was ninth between the ages of 15 and 25 amongst the autoimmune diseases. It was either the first or second greatest cause for years of life lost. It was behind other causes of death in these women and that would include diabetes, HIV, lung disease, anemia, cardiovascular and cerebrovascular disease and nephritis. But it still is, you know, lupus can be deadly and we know that. And uh but luckily we're getting more therapies. We're being more aggressive. We're limiting our use of steroids. I like the way lupus is going.
Another report, the final report for this podcast, was about drugs that target toll-like receptors. There are usually drugs out there targeting TLR7. This one — enpatoran — enpatoran is a small molecule inhibitor of TLR7 and TLR8, and was reported in the Willow study, a phase 2 trial of 463 patients with cutaneous lupus erythematosus, CLLE, or systemic patients who did not have extracutaneous disease, and they looked at whether this drug would affect the skin outcomes and measured that by a CLASI outcome score at week 16. So they either got placebo or the TLR7/8 inhibitor, and they showed that it was highly effective, with 50 to 70% better responses compared to the placebo.
So again this is important because toll-like receptor activation is very much involved in the innate immune response, which is important in the handling of viruses but also in the genesis of adaptive immune responses and autoimmune disease. There are mutations of TLR7 that have been linked to excessive activity that then leads to childhood lupus. So these therapies, which have been reported at the last few ACR and EULAR meetings, are getting closer to the market and I think that they'll be an add-on. And of course some people believe that hydroxychloroquine — one of its many effects, most of which are unknown and truly unclear, but we know it's good enough that we give everyone with lupus hydroxychloroquine because it's so safe — that maybe its mechanism of action is through inhibition of TLR7 or, I think, not nine.
So what about the safety of the TLR inhibitors? Looks really good. Nothing there that looks scary at all, and nothing learned from knockout models or mutation models for the toll-like receptors. So maybe it will compete with hydroxychloroquine for safety as well as efficacy.
Anyway, that's it for a long edition of this podcast. We're going to do it again next week. I want you to know we're getting ready to cover EULAR, which is about two weeks or two and a half weeks away. We'll be there. Hope you'll be following us. Hope you are going to enjoy that as much as you have in the past. Take care of yourselves. We'll talk next week.
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