Rheum with a View: Unraveling the Mysteries of Autoimmunity Seminar

Presenter: Dr. Jonathan D. Krant, MD, FACP, Rheumatologist at Monadnock Community Hospital

Date: August 21, 2024

As a rheumatologist and somebody who's obviously got a view, the term room of the view as you know alludes to that wonderful merchant film of years ago which I thought was great.
But all rheumatologists have a view as to what it is we do and I am no exception to that rule. A very good narrative should have a prologue. And the prolog I'll share with you is what my father did when he was a resident on the Harvard service of Boston City.
He became an academic oncologist and was a wonderful character, but his brilliant moment, I think, among several, was when Hensch and Kendall won the Nobel Prize in medicine in 1950 because their molecule was cortisol.
And The development of cortisol, the discovery that cortisol derived from the adrenal can make little old ladies jump out of their wheelchairs and dance was stunning. And if you remember the old Boston City Hospital,
those of you who are Bostonians, or Bostonians like I used to say, well remember that that old wonderful place had iron lungs back in the tuberculosis era. And so those of you who experienced one of those or saw them or actually heard of them know for a fact that they did exist.
You're actually in an encasement with negative pressure to expand your chest because your lung function was so deeply compromised. Cortisol got people out of the iron lung. It got people out of their wheelchairs.
And it was trialed initially in rheumatoid arthritis, interestingly. And Hensch and Kendall and Rechstein in Germany came up with cortisol almost almost all at the same time.
They're working in different places in labs and in academic environments. And it was revolutionary. But what does cortisol do? Cortisone, hydrochortisone, methylprenicillone, all of these different variants of steroid,
they render you osteoporotic, they give you cataracts, they cause hypertension and diabetes. They're not gifts. And my mentor at Johns Hopkins was Michelle Petrie who would say to me, you know, you You've got to have an exit plan every time you start a patient on steroids,
because these things are bad news in the long term. So for those of you who've taken steroids, you know what I'm talking about. And that leads us then into segue forward. Why would one take those lessons and become a rheumatologist?
Well, in my experience, I was a third -year clerk at UC San Francisco, a city I didn't know much about, but I was really excited about learning. And I was working with a fellow. After you finish your residency training,
you become a fellow, and the fellow I was working with is a guy named Dave Hellman. Got a phone call. There's a patient in the emergency room. Would you please come down to admit this 19 -year -old, a little short of breath whose kidney function is not quite right. And this young woman,
Gail, had progressive systemic sclerosis. And for those of you who know scleroderma or have heard of scleroderma, you know that it's a life -threatening disease, especially when diffuse and systemic as opposed to localized and limited,
and within three weeks she was gone. How could this have happened? And we did everything in our power to save her kidney function and her lungs, and even with high pressure ventilation,
we couldn't make a difference. Her disease was inexorable, progressive, and she died at age 19, engaged to a lovely guy, and her family was with her the whole hospitalization. I was there from the soup to nuts of this young woman's death.
And I can't do oncology like my dad. I can't become an infectious disease specialist. I certainly can't do general medicine. I have an investigative mindset. Rheumatology is my calling.
Many years later, here we are. And then what's happened in those decades that has really transformed our understanding about autoimmunity? Well, I have a whole series of slides which are fairly technical and I don't think that that's necessary or appropriate.
I'm assuming, and I am loath to make assumptions, but does anyone hear of a medical background? Nurse, physician, physiatrist, internist? Good. Well,
you'll calm to what I have to say, because I'm trying not to get so granular that I lose you in the weeds. The goal here is to understand where we've come from and where we're going. And the good news is,
and there's no bad news, The good news is we're right on the cusp of something really terrific. And I'll leave that as the hook in place now that I've got you riveted.
Why is it important to develop new therapeutics? Turns out that we're doing things that aren't molecular and they're not pharmacologic. There's a procedure called vagal nerve stimulation.
The left vagus in your neck articulates with your abdomen. And one of my classmates in medical school has developed this company that's developing a vagal nerve stimulator,
which stimulates the vagal nerve and patients with inclamatory arthritis. The talk between T cells and B cells which produce antibodies diminishes, that cross -talk.
How do we stimulate B cells from becoming plasma blasts, which are those cell types which, welcome, come have seats. We're just getting going. We're talking about the historical background of immune disease and immunology.
But the important point is that we're on the threshold of some really wonderful discoveries. We're talking about vaginal nerve stimulation. Turns out that in patients who are stimulated with a vagal nerve, but with a vagus and a signal transducer,
the rheumatoly arthritis gets better. Isn't that amazing? How's that possible? So, there we go. Novel approaches which don't necessarily involve pharmacologic manipulation.
That appeals to me because it's relatively simple, but it works. And the companies that are doing this now are becoming very excited. But that's just the tip of the iceberg, because the old standby developing targeted therapeutics back in the steroid day,
everything worked for about a month until you started developing complications of steroid use. And over the course of the past several decades, we've noted the development of disease modifiers,
methotrexate, mycophanilate, azithyoprin, hydroxychloroquine, plaquino. We've noticed the development of biologic therapies that are supposedly targeted, they target tumor necrosis factor,
the five TNFs, Enbrel, Humira, Remikage, Simpani. You may have heard of them or you may be taking them. They're wonderful if they work. Then if you fail them, we have oral immunomodulators like the Janus -Kinase inhibitors that you may have heard of.
Zeljans, Illumient, Rinvoke, the three commercially approved molecules in that class, which you can only use after you first fail to biologic because of safety concerns engendered by the Oral Surveillance Project in 2021.
But then there's IL -6s, actamra, there's IL -17s, secondinamab, cosentics, there's 1223s. There's all these wonderful mechanisms, some of which are marvelous in RA,
or lupus, or psoriotic arthritis, or ankylospinalitis, and some not. So what's the common thread, and where are we going? So I'm going to give you a hint. We need to interrupt the talk between T -cells,
T -lymphocytes, And B cells, T cells because they're thymic -derived cells, they mature in the thymus in human development,
B cells because they mature in the bone marrow, and B cells will become plasma blasts, which are antibody secreting. That may sound like a lot. But in fact, it's pretty elementary in terms of how we think about targeting this dialogue between T and B cells and plasma blasts.
And we're on the cusp with something really important, and as always, we're borrowing from our friends in oncology. So Maria, feel good because what you've been doing for years now is paying off. CAR -T,
chimeric antigen receptor therapy, targeting the CD -19 epitope. What does that mean? It turns out that there's a way of taking your own T cells. It's called autologous transplant, subjecting them to a virus,
what we call call lentivirus, expanding them outside the body, re -implanting them after you've conditioned the bone marrow with cytoxan and fludarabine, both very tough molecules to take,
and then watching as they wipe out B cells that carry a surface protein called CD -19. And we're now developing CD -19s, CD -20s,
that are very specific once you go through this phoresis program where you take out the cells, you infect them, they express a surface receptor for CD19 on the B cell surface,
which then is wiped out. That lineage is gone. And there's no transformation into plasma blasts, and plasma blast cannot therefore secrete auto -antibodies. And the key to the kingdom seems to be molecular in the sense that we're trying to target those antibodies that are pathogenic.
If you wipe out all your B cells, what happens? You develop hypogamaglobulinemia, a gamma -glob, which is commonplace in certain diseases that affect the bone marrow. So we give people gamma -globulin infusions,
and they work. But they're time -limited. If you only knock out those B cells which carry this very specific protein on their surface, then that lineage is deleted, and you're genetically not primed to make more of them.
So now we're building out these programs with CART CD -19, we're doing autologous transplant for patients who give up their own cells. They're transfected.
They develop a receptor. They bind B cells. They deplete them and the body is happy. And in 2021, George Schett and colleagues in Erlingen, Germany, took five lupus patients.
What are oncologists mucking around with lupus patients for? Why? Because We asked them to. We said, look, we've got these people who are not responding to standard of care. When you hear about conventional therapies,
that means how do we manage patients with these specific problems? Steroids, cytoxy and chlorambucil, those are inducing regimens. Then we maintain patients on drugs like isophthalophenylate and other what are called disease modifiers.
And we hope to get them into remission and we start taking things away one by one. And so the goal is to get people with no disease activity whatsoever on a minimum of medications to live a long productive life.
The problem with that concept is that 19 -year -old black, Hispanic, Asian inner city populations, rural Americans on the Navajo Res, rural New Hampshireites,
may not have access to these forms of therapy because either their disease is not recognized in time or it's not dealt with appropriately, and you have folks who are really suffering from the ways in which we've been taught to treat.
But it doesn't mean that the pharmaceutical world is deaf to these requests. They just need incentive and reason to pursue novel forms of therapy.
So we jumped the gun here. You remember the days back when HIV was prevalent in big cities, and ACT UP was formed a young, aggressive, vocal HIV -infected people to drive Congress to mandate pharma to develop antiretrovirals.
That fast -tracking process occurred overnight and it saved lives like crazy. We are now at the point where we can selectively target the T cells which are informing B cells to become plasma blasts.
We can target B cells themselves with monoclonal antibodies. We can then go after the products, those antibodies which are produced by activated plasma blasts.
So it may seem I'm very technical, and my slides have a lot of technical components, but let's look at who's impacted by these discoveries. The two quintessential disease states that I'll mention to you that you know already.
Rheumatoid arthritis, symmetric, inflammatory, polyarthritis affecting the small joints of the hands and wrists. Morning stiffness, fatigue, sometimes knowledgeable formation over the elbows.
Those of you who have R .A. or have had R .A. know this. Terrible disease. But it typically doesn't cause death unless you are so deeply immunosuppressed that you're liable to develop casual infections which can then end your life.
And that's a devastating side effect of some of the therapies that we use. Lupus, quintessential autoimmune disease, with high -todder antibodies to double -stranded DNA, which then bind complement.
When I was in the lab as an NIH research fellow, we did lupus testing on mice, who we gave proteins into their tail veins, which formed immune complexes that bound up the heart and the kidney and caused severe complications,
mimicking the human experience with lupus. Lupus occurs about 1 % of the US population. In some subsets of our population, inner city black, Hispanic, Asian populations,
it can be as prevalent as 5 % to 7 % approximate. There are genetic features of all these diseases. Lupus causes a malar rash, a red rash, sparing the nasal labial folds,
associated with severe fatigue, joint pain, devastating illness, mostly because if it's not the disease that gets you, the treatment does. Because the old way of inducing remission in those with lupus nephritis,
kidney disease impacting lupus, is to give cytoxan, cyclophosphamide, high dose steroids, followed by a regimen of mycophenylate, asophenylate,
asophyoprine, and so forth. And recent drug developments in the lupus domain have included drugs intervening interferon, which is one of the substances in the body which stimulate immune responses, so it dampens the interferon signature,
as well as other targets. Voclosporin you may have heard of. It's a molecule which is a calcium urine antagonist, another anti -inflammatory targeting lupus, but it doesn't impact on the cellular functions that produce these auto -antibodies that are so damaging.
Inflammatory muscle disease, Dermatomyocitis, polymyocitis, you may have heard of. You may have them. The antisynthetase syndrome. These are prevalent myopathies,
myasenia gravis. These are all diseases which are prevalent in the autoimmune domain, primarily because of the production of these antibodies, which seem to be the key to the kingdom.
So the pharmaceutical industry, instead of developing all of these sort of non -targeted anti -inflammatory molecules is now very, very keen on developing laser -like precision in the development of their research programs,
because guys like us are whispering in the ear of our congressmen telling them, get going. We can't lose any more people to these diseases. They're devastating. And it's not just black,
Hispanic, inner -city populations, it's rural populations throughout North America, Europe, Asia, and Africa. So I don't want to get too technical,
but I did want to mention that CAR -T is here. Chimeric antigen receptor therapy. I just got a call from a colleague at Fate Therapeutics. Would we trial their new therapeutic,
which is coming through human studies, called CAR -N -K, chimeric Antigen receptor, natural killer cells. To keep a very complex topic digestible,
there are two forms of immunity. One which you're born with is called innate immune response. Your skin, your tears, they engulf organisms. They do a great job. Natural killer cells are forms of lymphocytes which engulf and destroy cells which are infected with these pathogens,
these organisms that come from the outside. Then you have the adaptive immune response, where you have a bunch of cells which differentiate, depending upon what the signal is. The problem with autoimmune disease is that the body goes after itself.
It loses self -tolerance. How can a woman become pregnant and carry a fetus to term? Half that infant's genes are external to that woman.
She has to dampen her immune response. That's called self -tolerance. Otherwise, the fetus would be rejected, right? I mean, it seems obvious. But if you think about the mechanisms involved, you have to have a mechanism of inducing self -tolerance so you don't reject fetal tissue.
There are many such examples. But in autoimmune disease, of course pregnancy is not a disease state. But in autoimmune disease, We target our own bodies as foreign. The mucosa of the oropharynx,
joints, the lining of the lung, kidney, heart, brain, and all the disease that you see, seizure activity, myocarditis,
pleuracy, inspiratory chest pain because of these autoimmune mechanisms are very commonplace in people with autoimmunity, like lupus, like R .A. Thank goodness I already not so much because it's so prevalent about,
oh, maybe three to four percent of the US population today. Whether or not you have antibodies that show it, they're there. And when you give things like CAR -T or bi -specific antibodies or neonatal FC receptor therapies,
there's a whole host of approaches to managing which are now in evolution. They're not even in the market yet. I consult a lot with the pharmaceutical industry because I'm keenly interested in what's coming. That's going to be off -the -shelf available to our patients in the community and not just in academic centers where these things are promulgated and stimulated So why don't I stop for a moment catch my breath and ask
questions? Have you asked me questions? What burning questions come to mind? I have one. Please What's the difference between rheumatoid eye rheumatoid?
Beautiful question. So the distinction is strictly serologic. The presence or absence of a rheumatoid factor or citric -related polypeptide. These are proteins that are elaborated by the patient with RA.
The phenotype that is the physical features of RA, symmetric, inflammatory, small joint disease are identical. It's just the presence or absence of an antibody, which we think is pathogenic.
It induces disease activity. So a seronegative patient is treated just like a seropositive patient. We call them rheumatoids. We just say it's seronegative. Why? I'm not sure. Because if they're treated the same way,
why do we distinguish? Question mark. That's beyond my pay grade. But I'll tell you that it's distinction. In terms of the distinction, some companies would herald a class of drug like the co -stimulation blockers,
abatacept, Arencia was promulgated as the biologic therapy for patients who are double serop -positive, rheumatoid factor and CCP antibody positive.
But there are plenty of people who don't manufacture those antibodies, but have others that are causing damage, which are targeted by the TNFs, the IL -6 therapies like actemra,
co -stimulation blockers like Orencia, and finally Rituxan, which is a CD20 antagonist, it beats up on those B cells that have that protein marker. But just answer your question,
there's really no distinction. We treat it the same way. What else? Diabetes. Is diabetes an autoimmune disease? Absolutely. Especially insulin -dependent diabetes,
where we're using molecules to attach to stimulate pancreatic beta cell production or... Stroke alert, room 8 ED. Stroke alert,
room 8 ED. Stroke alert, room 8 ED. So where do we see strokes in medicine? In lupus patients, lupus patients who have hypercoagulability,
about 10 % of our patients with systemic lupus have autoimmune hypercoagability. First your spontaneous loss, deep vein thrombosis, a clot in the leg, it can promulgate and cause a clot in your lung that's called a pulmonary ambulism,
stroke, heart attack, young people. You look at the pro -thrombin times, with the prolonged, we do a one -to -one mix with normal serum, if it doesn't correct, they have a circulating anticoagulant, a prothrombotic protein,
which we need to get on top of, and we can. We can save lives by looking. But if that was a stroke patient under the age of 50, my first question is, do a partial thromboplast in time and a prothrombin time?
Make sure you look at their platelets. Could it be a lupus which is manifesting as a stroke as the first event? Just the thought. Other questions, please? What about Shogrens?
Hotest topic today in medicine. Shogrens, as you know, is a disease characterized by the presence of high -tider anti -row antibodies. What does that mean? Dry eyes,
dry mouth, fatigue, joint pain. 10 % of Shoggins patients will develop interstitial pulmonary fibrosis, lung involvement. Berringer Ingleheim has developed a drug called Ophev,
Nintedinib, a drug I like, but the primary outcome measurement is lengthening the duration of disease symptoms once established. My goal is to get analytics or diagnostic testing done so we can identify those at risk for developing lung involvement before they do and start treating them with antifibrotic therapy.
And then they don't have that phenotype. So there's a class of drugs, the neonatal FC receptor antagonists, F -gartygimod is one, for neuromyelitis optical spectrum disease. It's already approved.
And the trials that are being conducted now by the companies that are making these drugs are excellent. Argenics is one. They make Vivgard for neuromyalitis,
but it's going to be approved in chogrens. We treat it with molecules that increase secretions, like sialagogues. We call them sialagogues. Ivazac is my favorite.
That's a very potent molecule in efforts to get those cells in the tear ducts and in the salivary glands to produce. But oftentimes they don't.
And so dry eyes leading to corneal abrasion is not uncommon in people of chogrens. The dreaded complications are B -cell lymphoma, perot enlargement, regional lymph node swelling associated then with B -cell lymphoma,
and it's very treatable, but in some patients it's not a good thing to have happened in almost all cases. We need therapies that identify those at risk for developing lymphoma and interstitial pulmonary headache,
nausea, ferv, no medications are without risk. I mentioned CAR -T as especially autologous CAR -T,
where you take your own T cells, treat them, re -implant them. CART is associated with what are called ICANs and CRS, ICANs, seizure, dizziness,
central nervous system effects. They're modest, they're treatable, But you don't want to be the patient who develops that problem. So it's probable that that form of therapy will be restricted to people under the age of 50 only because it's a rigorous process to get a phoresisone where you have your cells removed,
expanded, re -implanted, and then get your marrow conditioned with a regimen, including cytoxin and fluidarabine. It sounds terribly complicated, but it's not inconceivable that we can start doing this in a community hospital setting.
Novel concept. We don't even have a clinical research unit yet. But it's something which I'm very, very excited about, and maybe an opportunity for us here. We'll see. We'll see what the board of directors says. There's a member sitting in the back.
But what's so important is that you understand that nothing comes without cost. Does society have the resources to develop these assets? Do we have the initiative to implement them when an approach like Carty costs a million dollars a year?
Imagine what that's like. How's an insurance company gonna pony up a million dollars for one patient? The average biologic, be it Enbrel, Humira, remikade, simsia, symphony, the five of the TNF class or the IL -17s,
you've heard of them. Skyrizi, Rizzi, Rizan Kizumab, which is a great drug for psoriotic arthritis. I use a lot of it. The newest do crevasidinib, which is a injectable therapeutic for psoriasis.
These drugs cost $50 ,000 a year, average wholesale price. It depends on the relationships with our pharmacy and acquisitions of these things. But for the patient who's got a copay cost of $1 ,000 every two weeks,
that's overwhelming. How does your average person cough up $25 ,000 in a year just be treated? Because it's a carve out of their indemnity plan. We don't have good answers to this.
We ask the insurance companies to cover. They don't because they're interested in paying their corporators and being profitable. I shouldn't be so cruel.
They often do, but they often pay only a percentage. Then we ask the drug companies themselves to provide cost amelioration, co -pay cards, which you may have seen,
things like manufacturers discounts which help. And there's foundational support through other places, the arthritis foundation for one, the Shogran syndrome foundation, the lupus foundation,
the rheumato I mean, we all have foundations. They're everywhere. And they're constantly calling me. Are you using this or using that? Are you talking about this with your patients? It's nonstop. The inbox is choked with information from foundational support so as to get access for patients,
which I think is very legit. So where are we going? I think that we're close to being able to say with security that we may be able to cure patients with autoimmune disease.
And the initial hook was these auto -antibodies. What are we doing with patients who are producing these high titers of rheumatoid Rheumatoid factor, anti -double -stranded DNA, anti -Roe in Shogwins. If we can eliminate that B -cell population that produces these things,
can we reverse disease? All right, it's tough because one of the things we look at is progressive deformity, joint space narrowing, loss of bone substance across the joint erosions.
And you'll see this. You'll see it in your own hands. What I've got in my 60s are Hebronins and Bouchard's nodes of osteoarthritis. Commonplace. You know, everybody's got them. It's inevitable. Don't ask me why,
but that's just what happens. But RA is inflammatory, puffy, swollen, warm, tender. You lose the inneroscii, the musculature, and the dorsum of the hands. You lose the ability to grip.
And then your functional assessments fall off because you can't hold a fork. So we have whole companies that are devoted to assist devices to help our patients with autoimmune disease. We don't see that much of that anymore because we're aggressive in terms of management,
but I don't want our patients taking steroids for all the reasons we've discussed. So how then do you mix, it's inevitable that we do, and for those of you who are on steroids, forgive me because I've probably done it to you or will at some point.
That said, we're always looking for a way out. Maria knows because I'm always talking about how do we get this patient off steroids, We use some combination therapeutics and be smart about approaching their problems. But the real key is communication.
And at the end of the day, I've got to hear from you. You've got to say, look, this isn't working for me. It doesn't mean I don't want to get better, but I'm on a can all the time, or I'm peeing three times a night, or, you know,
I'm losing my hair, or I can't eat. I've got constant gastritis from the medications you're giving me. Non -steroidels. How many of you take non -prescription nseds, ibuprofen,
naprosin, meloxicam? Does anyone not? I mean, the problem, of course, is if – Well, there's answers. We can talk about it. The problem is that people are fairly blithe in their consumption of over -the -counter meds.
If you're on a protocol, that is if you're enrolled into a clinical study and you violate the terms of engagement, you're dropped from the study. But we don't assay for that unless your urine's being looked at periodically.
We don't test people taking ibuprofen. We just, are you taking it or not? Do you know what the potential risks are? Kidney failure, GI bleeding, and a host of other things.
Be careful. OTCs are not your friend. The general sense is, don't be blind with medications. It doesn't matter what they are. They all come at a price. And so we're sensitive to that,
and we're trying to get you to consider what are the terms of engagement. And I can't know that until you tell me, you know, I just can't take this stuff. Or this is unbelievable, it's doing such a great job.
And my immediate response is, oops, you like it too much. That was clearly the case with opiates. We don't give opiate analgesics anymore. If we can avoid doing so,
if you've had a hip replacement, that's one thing. I'll be calling you every 12 hours to make sure you're cutting down on your dose. There's a new class of drug called the NGF antagonists, nerve growth factor antagonists.
NGF was described by Rita Montalcini in 1940 right in the heart of the Second World War. She was under house arrest because she was Jewish in Rome and she was spirited out to go to special surgery in New York by a fellow investigator who was looking at NGF,
nerve growth factor, turns out that antibodies to nerve growth factor eliminate pain processing in the brain. It's non -addictive, it's cheap. It's been cloned,
the genes that produce the stuff. We are now at a threshold where we can give patients, NGF injections. Fulranomab was the prototype now, it's tenazimab being developed by Lillian Pfizer,
and I was on the FDA panel that adjudicated this because if you took teneasmab, or fulranomab back of the day is now teneasmab. If you took this medicine with nonsteroidels, you would develop sponk.
Does everybody know what spank is? It's a great name. Spontaneous osteoecrosis of the knee, sponk. So people taking ns and NGF injections would develop death of bone,
be it knee, your hip. If you controlled for the non -steroidal, no one got Spock. So Spock is the thing of the past, and this is going to come on the market in the next quarter to a year. Somewhere,
it's in the middle. It's in phase three, that is, it's in registrational trial before the FDA. And I'm still adjudicating for the FDA because of the remarkable ability to eliminate opiates.
Right? Hydrocodone, oxycodone, oxycontin. We have an epidemic of opiate abuse in this country. If we can eliminate that class of drug, I will be the first to sign up. Other issues,
concerns. Please. Yeah. use for all kinds of elements.
So is that a point or a question? I guess both. Okay, good. It's role in autoimmune and if you could explain and blame in terms, if you will. Of course, so monoclonals,
being a big user. In fact, I'm sure that's why I was hired to stimulate our monoclonal antibody use because it's a profit center for the infusion suite. I'm being sarcastic. We love monoclonals because there's such wonderful targeted therapies.
But as mentioned in lupus, in Wegener's granulomatosis, now called granulomatous polyangiitis, in so many of the diseases that we treat, we're using monoclonals that have been so refined that they're given subcutaneously,
not just necessarily by infusion. And there will be new iterations which bypass the gut, though they can be taken by mouth so they're not digested in the stomach. They're proteins.
They're grown up in a vat. So monoclonal is a derivative of a protein which is cloned by a cell, a vector goes in to expand the production of antibodies in a plasma blast,
cultured up in a vat in warm temperatures, and it takes a while to get the stuff. And as you know, there's now biosimilar versions of reference compounds like adalimimab,
humira, etanercept, enveral, toxin, roxians that are about 20 or 30 % less expensive than the reference compound. The immune checkpoint inhibitors that you guys use in oncology are probably getting genericized as well.
I don't know that literature as well. But the monoclonals are becoming cheaper and cheaper. They're in the 50 plus $1 ,000 AWP range, annual wholesale price range. But their ability to transform diseases unheralded in human medicine,
especially in autoimmunity. Remembering that Schet and Matheson and colleagues in Erlingen in Germany are now using CART, CD19, and lupus nephritis,
and scleroderma, people are going from being on -death store in renal failure with intertitional pulmonary fibrosis, ground glass opacities, restrictive indices on pulmonary function,
to walking around playing ball with their kids and having a normal life. The five women all age 50 with lupus nephritis, membran or proliferative, diffuse proliferative histologies,
that's bad. You don't want that. If you have lupus don't get nephritis, you have nephritis don't get any of these bad subsets because it's not a good thing. We don't really know what to do with them, but now we have the tools to render them disease -free.
They heal up their lesions in the glomerulists, their GFRs improve, their creatinines drop, their urine protein -cratin ratios normalize. Unbelievable. What a transformational moment.
So I share my enthusiasm because we're on the brink of something really special. I'm not asking for your political support. I'm not going up for Congress. I'm asking for your understanding that as we speak about these things,
don't sit passively and go, oh, that's nice, ask questions, understand why we want to build out these very specific targeted programs because they're really saving lives and transforming people's experiences.
If you can get rid of lupus and get rid of rheumato arthritis and chogrens, be it primary or secondary to underlying autoimmune disease, like lupus or RRA. Soriotic arthritis.
Great example. We don't yet know exactly what the antibodies are that drive the disease state. But we do know that keratinocytes and skin, the dermatologists talk about keratinocytes. I talk about synovocytes,
the residential cells within the joint space, that elaborate all these inflammatory cytokines, tumor necrosis factor, interleukin 1, interleukin 6, 27, 12, 23, all these cytokines are playing havoc with the patient's body because they've lost self -tolerance and these tissues are deeming their residential surroundings as foreign and they're attacking and they produce habit.
Warmth, redness, swelling, tenderness, redness is impressive in psoriasis. If you've seen big -time psoriasis, with Passi scores, psoriasis The Minority Index, people in clinical study have 50 to 70 % body surface area involvement.
They're bound, they can't move, their psoriasis like armor. They have skin like you within weeks of treatment with some of these very targeted monoclonal antibodies that we're using.
Skyrizi. I was one of the principal investigators in the Skyrizi trial. You hear it being advertised. Other questions? I've seen you before. Maybe it was at the meeting in...
I met you several weeks ago. True, true that. Because I've lost my rheumologist over a team. Well, that's not good. Understood.
Welcome, Pilgrim. We're happy to see you. Nice to see you again. It's to see It's probably on the rheumidone and the ureva. It's,
yeah, yeah. I met with the second rheumol. Yeah, Ralefin is a challenging drug. It caused a lot of GI distress. When you couple that with a PG -4 antagonist like Arava,
Lafluenamide, you're going to be bound in the bathroom for weeks. Most are, some aren't. You're lucky. It was a cardiology that you're concerned about.
Ah, yeah. Well, you know, look, as I said, every medication comes at a cost. Whether it's an over -the -counter non -seroidal or a prescription monoclonal, there's always a price to be paid, right?
So our goal is mitigation of toxic side effects. We call them treatment emergent adverse events, TEAE's. Do you know of a specialty medicine that doesn't have these acronyms? I mean, we're rich with them,
which appeals to me because I was an English major in College. How do you know that I wasn't? Another foolish acronym. Avas?
AFA. Good for you. I love it. Other questions, concerns, points of view.
This information is all very, how do you get yourself diagnosed. Wonderful. In an area like, I mean, you know, I grew up here, but I was gone a long time.
Yep. Yep. When you, I mean, we have, we're lucky to have this facility here, but I've had some strange things, but I've had to go to Boston for it. Going back and forth all the time is...
It's a challenge, and it's a long drive. I get it. You know, you need the ear of an experienced clinician to understand what you're talking about. Osler said,
I can make a diagnosis by walking in the room before I touch the patient, by looking at them. But my mentor, Bill, back in the day a century ago, did not have the tools we have today.
And it's pattern recognition. If I look at you and you've got a violation discoloration over the eyelids and purple knuckles and You can't stand from seated position,
your next trip is to the path lab for a biopsy of your muscle because you have polymyocitis or dermatomyocitis and nothing else does this. But you don't get to the point of recognizing those things right out of residency or less medical school unless you have a gift which transcends clinical medicine.
The clinical experience is an immersive one and it's interactive. And if you say to me, Dr. John, I'm concerned because I'm stiff when I wake up in the morning. I've got this funky rash that comes and goes.
I can't swallow very well. But by the way, I've got these features that would suggest something else maybe. I mean, I've got this swelling in my small joints, and I look at you and I see a malar rash,
puffy, MCP, PIP joints. My comment is, you have rupus, rheumatoid arthritis and lupus in combination. There are overlap syndromes in autoimmune disease.
How's an internist going to know this? How's a family practice doctor to know this? They listen to talks that I give and my colleagues. There's 4 ,000 rheumatologists in North America. There's 4 ,000 cardiologists in Boston where I'm from.
This is not right. We need your help in providing initiative to, It's not just the American College of rheumatology, it's to your congressman.
We need funds to be able to drive training programs. Rheumatology is not easy. It's a subset of medicine which is really exacting because we don't want to be giving drugs to patients that don't deserve them.
Not that they shouldn't get them if they do, but we need to have very strict criteria by which we judge, right? All this stuff. Oh, so someone was playing with my slides. That's great. That's good,
Rob. You must be bored. Yeah, see, I mean, look, everything is pretty complicated, but look at all the organ systems that are involved. The point is that you don't get to be good at this until you've done it for some time.
I don't care how smart you are or where you went to school. What I care about is, are you good? I am deeply physician -averse. My wife thinks I'm out of my mind. But the reason for it is that I just worry that someone's not experienced enough.
I have a son who's becoming a pediatric neurologist. He's really written three papers. He's in his internship year. And he just graduated from University of Vermont. This kid has decades before I would even consider referring someone to him even though he's a good -looking smart former US key team member.
You get what I'm saying here, right? So other questions, Other concerns. So should we be contacting? Yes.
Your reps, you know, whoever is your conduit, please provide funding for X, Y, and Z. Please help the training programs for postgraduate education.
I'm on the Global Engagement Committee, the American College of Rheumatology. It's a rarefied group about 15 of us who come from countries all around the world. What are the standards of care in China and Japan,
in Finland? Is Africa even represented? You know, we have deep socio -cultural disparities everywhere we go. And if you're not sensitive to these distinctions,
you don't understand how much morbidity there is out there and folks who are not recognized. Your point is so well taken. I need to be recognized. Hear me, see me, touch me,
know who I am, know my biases, know my predilections. How do you get there? You ask. You have someone like Maria who comes into the room and says, Dr. John, we've got this patient who is a blah,
blah, blah, blah, blah, blah, blah. You've got to listen to every point of that that's being elucidated because that's critical in your understanding of who this patient is and what their preferences may or may not be, and then you explore them.
Would you like an intravenous injection? Absolutely not! My mother died on metatrexate. Oops, well that I can be taken by mouth or by injection, but you know that metatraxate's not on your list. What are patients' preferences?
What are they willing to do? How far are they willing to drive? We have an unlimited upside here. We have an infusion center. We have an oncology unit. I've joined the oncology group because that's where I belong.
We're using all these fancy medicines. But to gain access, you have to meet criteria. It's not random. It's a deliberate process here. And I'm very deliberate.
To make this personal, I've had joint aches for years now. I was very athletic. I thought, oh, it was old. But when I went to Boston for something else,
I saw a rheumatologist and they put me on some, that's when they told me I had zero negative arthritis. They put me on something called lyrica. Pre -gabalin, great drug. It's a pain drug in the arthritis setting because lyrica like gabapentin is a modulator,
but it's not for everyone. It can be tough. It can cause dizziness and a lot of accurate. And in young women, women causes weight gain if you're giving Lyrica for fibromyalgia and someone comes back and says I can't fit in my clothes and I'm 30 years old what does that mean to you you should tell you that I'm not taking your medication I've been given anything else and that was four five years ago oh no but there's
a lot of options we'll talk about this a lot of lot of options but I'm just saying that that's one of the I was so glad to hear that we were getting a rheumatologist I've seen you once and I put the good word up like I don't Other Other questions,
other concerns. Can you all afford your medications? Yeah. You know, that's the rarity.
We are trying to navigate this difficult landscape with payers that don't want to pay. It's not because they don't want intrinsically to pay. They're trying to conserve resource. But these medications that we're talking about are extraordinarily,
extravagantly expensive. Residents out of residency have no clue about cost. What does the cost to prescribe this drug? They're told by their attending physicians. They become attendings.
They better listen, otherwise they're out of a job because no one will see them because they can't afford to go. So you know, there's all these interplays and they're worthy of consideration. The economics, The culture,
the biases of the people you're caring for, these all come into view. I mean, I've always liked working in rural America. I love my fancy Ivy League training. But when it comes to the personal engagement with an individual,
all that stuff falls to the side. How can I help you? If you don't have that, it's not part of your DNA. You don't belong in the business. Other questions?
Have I bored you all to death? All right. Yes, ma 'am. That's such a great question because it interfaces between the clinician,
the physiatrist, the physical therapist, the OT, you know, all the important folks in the room. Those are the people who have hands -on to the patient, not just writing prescription for them.
Movement. As we get older, we lose adequacy of hydration in our soft tissues, muscle, tendon, ligament. So even slightest movements getting out of bed standing from a seated position can result in a bad back or a sore calf.
Why? Because people are relatively dehydrated. They don't know it, but their tissues are liable to soft tissue injury. And that amplifies when you start ratching it up.
It doesn't mean you shouldn't exercise though. There's non -weight -bearing opportunity. The pool, the jacuzzi. We have two pools here, right? But the pools are, the pools weather,
no matter where you are, are fabulous. There's a lot of potential for adjuvant therapy, myotherapy, hot rocks myotherapy is something that I've utilized. Amazing.
People put literally warm rocks on places that hurt. Increasing blood flow to places that typically lie dormant. Using those muscles that you do have, it doesn't mean build up your quads, hammies,
and calves to go back to your high school college wrestling career. That's not happening. I wrestled 166. I'm nowhere close to that weight -wise, but I was a D1 wrestler.
And I miss those days, but I don't miss getting beaten up all the time. Same thing with the cross. All said, all said, age -appropriate recommendations for activity are my recommendation because I think that movement precludes contracture.
And it doesn't matter where you are, whether it's the small joints with the hands and wrists, your hips, knees, movement is in your favor. To the extent that you can do it, do it. And let,
you know, the simple song is, if it's painful, then back off a bit. Talk to people, get a program, get referred. It's all reasonable stuff. But does that answer your question? Yeah, I mean,
the more movement I think the better. Personally, ma 'am. What about a diet? Great. So if you're a coal miner in rural West Virginia and you're on the pipelines or you're in the mines and I'm talking from experience here,
what is the number one diagnosis in 20 to 25 -year -olds in the coal mines of rural West Virginia? Nowhere close. Thank Thank you.
Why? They drink beer. Oh, I love this woman. Absolutely on target. Absolutely on target. Know your audience. Exactly right. So you've got these 19 -year -olds with toafaceous gout.
They've drunk themselves into renal insufficiency. There's serum uriates in the 10 to 12 milligrams per decolary range. You give them alpurnol and what happens to the serumurate. It goes up because they don't take it and they drink more.
Why? This is their culture. Alcohol is intrinsic to the West Virginia diet. And it doesn't mean Parkersburg, Vienna, or down south to the Kentucky border.
Everybody drinks alcohol. Not to say that we don't do that in New Hampshire. But it is to say that if you're achy, tender, sore, your primary care doc is probably saying, hmm,
let's check your syria and look at your 25 -hour urinary excretion for monosotium ureate. If they're not, they shouldn't be your primary care because this is common stuff. For the folks who have real troubles with high serum urates who'd lack adequate renal excretion and they're overproducers are under excretors,
most people are under excretors. So the goal is to increase urinary excretion of monosotium ureate. You can push that to a point. We're not using a monoclonal antibodies called pegalotechase, which is pegolated uricays.
Euriches, you know when you go to the beach in the summers, which we're rapidly losing, that is this time of August, I mean to say. And you see pigeons and birds and seagulls excreting white pellets from their mouth.
That's urate. They don't digest it. It doesn't go through the cloaca. It goes into their oropharynx and it's excreted this way. My wife's a veterinarian, she keeps trying to teach me how this works and I have a hard time with it.
Humans can't. So if you reach the saturation coefficient, which is that level of monosodium urate crystals in the bloodstream and exceed it, it's like what your mom's used to do, or maybe you still do,
or your dad's, making sugar candy. Remember you supersaturate a pan, keep pouring sugar into boiling water. And at a certain point,
it doesn't go into solution. It precipitates. That's the saturation coefficient. Your blood is exact same way. At 986, you have a certain saturation level, about six milligrams per decilator,
in which you're causing urate candy to form inside your joints. So if you have high serum ure rates, the goal is to lower it, and alipurinol and phoboxostat do just that. The sine you're at is a uraat one.
It's a transport mechanism to increase renal excretion. It's popular in Europe. I think it's banned by our FDA for reasons I don't understand. Now we have Christexa, 8 milligrams IV every other week,
indefinite, premedicate with a drug called mycathenolate or methotrexate because antibodies formed to polyethylene glycol, which increases tissue penetration. Great stuff. Who brought this,
who thought of this? But I was on a panel about peg lotocays maybe 10 years ago. And there were three patients. One of them was Jim Belushi. What a riot of a guy.
He'd been on Christexa experimentally before he was being treated once it was a commercial asset. It's gone through many different iterations. Jim Belushi like his big brother John, big time drinker.
Jim is still with us, so I'm not going to talk about how much he drinks or what he drinks, but he drinks too much of it, and eats a lot of organ meats and doesn't pay attention to his diet. So a lot of gout management is diet, a lot of it is alcohol use,
and a lot of it is paying attention to your medications. But physicians feel they can just keep pushing alipurinol and people who don't respond. That's where the next generation medications becomes important, plus diet, plus advice about staying well hydrated and all of that.
It's relatively simple, but it's very quantitative. It's appealing to me, but we don't have a lot of gout yet. It's hiding. We'll see it. What else?
What about osteoarthritis? Does everybody know about OA? Because you're going to get it. You're bipedal. So by definition, you're going to develop osteoarthritis. And it may be a large weight bearing joint like your hip or your knee.
I had my first knee done by the head of the US ski team orthopedics In Seattle, when I was a research fellow at University of Washington 20 years ago, then I had my other one done 10 years later.
I really admire people who have bilateral knee replacements at the same time because you put yourself out of all the misery of the protracted convalescence and the pain. And I was liking Delaudid too much.
I'll tell you that pain meds are addictive in the post -operative setting Because you become very habituated very quickly. And Dilaudid hydromorphone is an amazing drug. But it is really bad news,
especially when you become too fond of it. If you get too fond of anything and it's not someone you're married to, that applies to drugs as well as to humans. What else?
Questions, concerns. Stock tips. Nothing? Please. Always getting sick.
And I seem to have sinusitis all the time. And I do, I've been doing it for a long time. It looks like a turkey baster.
I use it twice a day. But in spite of it, I'm constantly having stuff go down my throat. And my bronchial tubes are always throat.
And I can't swallow so it gets stuck. That's a problem. Do you have an ear, nose and throat doctor you're working with? No. That would be a good thought. You know, there are conditions in which you have diminished immunoglobulin which lead to recurrent nasopharyngeal infection because you're not fighting it off adequately.
Some forms of oglobulinemia can be associated with recurrent rhinocinocytis. It's not my area of expertise by a long shot, but quantitative immunoglobulins might be a start immunoglobulin assay.
And then a look into your nasal cavities to see what's going on, maybe even a biopsy. You may have one of these unusual diseases, I won't mention their names,
which are associated with recurrent nasopharyngitis. I would bring it to your doctor's attention because you need an ear, nose, and throat doc. Thank you. If you have high -tider anti -rural antibody,
this may be a form of chagrin's, but I've not seen that specifically in the setting of chauvin's. Again, I think that your best gambit is an E &T doc. Okay. Yeah. Or an allergist.
They both make sense. Other questions. You had mentioned that diabetes associated with the soil. Yeah. I wonder if someone gets Lyme disease,
I've been told the Lyme disease can wake up later and kind of come back and give them the whole symptoms and go over the whole thing again. Oh, you're asking a whole lot of very interesting questions to unpack. Can I unpack some of this?
Sure. Diabetes inherently, first off, the chromosomal locus is on the six chromosome, the H -L -A -D -R -4 locus. It's a genetic strip of an allele,
two -paired genes which sit in one place, which are disease susceptibility genes, and R .A. and diabetes keep company, as does Hashimoto's thyroiditis, thyroid disease.
Curiously enough. As regards Lyme, I used to be the head of the New York State Task Force for Lyme disease. How I got stuck with that is beyond me. Because Lyme is one of the most difficult things to understand.
You allude to chronic persistent Lyme. If you have 28 days of and 100 milligrams twice a day for 28 days, your risk of having persistence of disease activity is virtually non -existent.
It doesn't mean you can't have suppressive complications kind of like long COVID. Is there long Lyme? People have been talking about that forever and physicians have been poo -pooing it forever because we do CSF.
We look for neuroborreliosis. We don't see evidence of Lyme anywhere in the central nervous system, especially if you take, do a lumbar puncture. So where is it? Why are you having these headaches and this dizziness and these symptoms of shaking chills fever,
even joint pain? I think what happens in Lyme is that an immunological reaction happens, antibodies are produced which attack the organism, and there may be debris in the process which continuously stimulate at a very low level in immune response and we're not paying attention to it.
And why is that relevant? Because when you use Plaquino hydroxychloroquine, as we do in chogrens and in lupus and other diseases like them, those symptoms melt away. And why is that if it's not immunologically mediated?
It's not anti -infective. It's not an antibiotic. It's not septriaxone or doxycycline or a mox. It's another approach, but it suggest that there is a subset of patients who develop chronic persistent antigen stimulation of our B -cell repertoire,
and that plaquinole is good enough to make a difference. Best I can do. But I've done it. I'm just curious if it was categorically. If the Lyme is lying indolent,
you get diabetes, and then the Lyme goes haywire, I've not seen that. But I've seen a lot of Lyme when I was in the Adirondacks with Cindy McGuire. Lyme disease is an endemic there.
My wife treats Lyme and dogs. So if you live with tall grass, you'd best be wearing DDT on your lower extremities. If you're a fisherman in the summer months, you'd best be thoughtful.
What else? Other concerns? All right. Thank you. Thanks for coming out. Did we show pictures of what Lyme looks like,
what lupus looks like? We sure did. Oh, good, okay. Did you know what it was? Go back just for a second. So lupus, again, red rash sparing the nasal labial folds,
sometimes oral ulceration is featured, and show R .A. There's an already slide here somewhere. There we go.
So look at these hands. Notice how the distal interphalangeal joints are spared. What are the three things that cause DIP joint arthritis? Anybody? Hebriden's nodes of osteoarthritis,
right? Soriasis, psoriotic arthritis, Gout, interestingly. The MCP joints, these guys,
often the second and third MCP joints and the PIP joints are involved, look at how contracted this finger is. That is, you've got a cock -up deformity right there.
And look at how prominent this extensor tendon is. But look here at the wrist where the tendons are atrophied, they're atrophic, Because the musculature is targeted, it's a very odd phenotype RA. Whether you're rheumatoid factor positive or negative,
these patients can be very progressive. Deformities are often symmetric. Look at how it's a fourth finger in both hands. MCP second third, PIP, second third, in this case fourth.
Wrist involvement. It's a very typical presentation of ORA. Lupus doesn't look like this. Osteoarthitis doesn't look like this. It's classic.
It's a rheumatoid hand. You'll recognize it when you see it. Thank you again. Come by any time. If I'm in the middle of it, I probably won't have much time to chat,
but otherwise grab me and we can talk.