Novartis ianalumab receives FDA Breakthrough Therapy designation for Sjögren’s disease.

0:00 Hi, thanks for tuning in and watching episode #145 of the Doctor Podcast Show. I'm your host and creator, Doctor podcast Doctor Robert Seikert. Please subscribe to and follow Doctor podcasts and please like, repost and share this episodes with your friends, family, coworkers. They'll learn a lot. If you have any comments about this show or anything else, please send them to me as well. I'll be sure to reply to you. Today's topic is about an autoimmune disease that has been underdiagnosed and neglected for a long time, but is finally being recognized and treated with a better understanding.

0:35 It's called Shogren's Disease. Our guest today is Doctor Sarah McCoy. She is a leading rheumatologist, physician, scientist, and one of the nation's top experts on Sjogren's disease. Doctor McCoy is an assistant Professor in the Division of Rheumatology at the University of Wisconsin School of Medicine and Public Health in Madison, WI. She directs the UW or University of Wisconsin Health Sjogren's Disease Clinic, only one of a few handful of specialized clinics in the entire USA and one of just two in the Midwest, and that draws patients from all across the USA.

1:10 In addition to seeing patients, she built and leads the UW Madison Sjogren's Biorepository, a vital research resource, and she's also on the Sjogren's Foundation Board of Directors. Her research focuses on understanding exactly how Sjogren's develops so we can create better diagnostic tools and ultimately better treatments for patients. With her unique blend of clinical care and cutting edge research, Doctor McCoy is in the forefront of transforming how we think about and treat this autoimmune condition.

1:43 So Doctor McCoy, thanks very much for joining us today on the program and sharing your knowledge and experience about Sjogren's disease and the new medication that we'll talk about specifically for treating Sjogren's disease. Thanks. It's my pleasure to be here today and thank you for having me. Sure. So for the audience who may not be familiar, can you explain in in simple terms what an autoimmune disease is and why our immune systems decide to attack our body's own tissues and organs sometimes?

2:13 Right. So we all need our immune system to fight off viral infections and bacterial infections. But in autoimmunity, something goes wrong and your immune system starts recognizing your own body as foreign and tries to eliminate it just like it would any virus or bacteria. Now, why this occurs, that's a great question. And it's sort of disease specific in the context of Sjogren's. Usually there's a genetic predisposition, but it's not all genetic, just a little bit of a genetic predisposition and only in some patients.

2:44 And then we theorize there's a second event or a second hit that drives actual disease progression. And that might be a virus, it could be sun exposure, could be stress. That's something that we're still trying to work through right now. So we we haven't quite figured out what triggers this and and different people that sometimes the immune system just goes awry and goes overboard and attacks our organs. You got it. Yeah. And and like I said, just stress sometimes can do it. It really is person to person, highly variable.

3:14 That's also an area of hot research. So we're trying to figure it out. Right now, where does the name Sjogren's come from for this disease? Oh, man, that's, that's a great, it's a great historical. I have to tell an anecdote before I get to Henrik Sjogren. So Sjogren's, you know, it's a disease many of us are passionate about. And the first patient who was described to have it was presented in the literature in the 1800s and 1888. And she was a woman whose tongue was cracked and dry in all directions, like crocodile skin, and her eyes were so dry she couldn't cry tears.

3:47 And she was treated with a tincture of a plant called jabarandi plant. And that is a drug modern day called pilocarpine, which is the same drug we use. So I always start my history lesson with saying the primary gold standard treatment that we use today, we use in our very first Sjogren's patient in the 1800s, showing the the slow rate of of progress we have to treat the disease. And then in the 1930s, Henrik Sjogren came along with his wife, Marie Sjogren. They are both ophthalmologists and described the first series of women who had severe dryness, half of whom also had rheumatoid arthritis, which is akin to sort of the distribution of the patients we see today.

4:28 And he defended his thesis with this cohort that he described and ended up going on to spend his life studying this disease. Wow, that's a fascinating story. And of course, ophthalmologists always discover everything right. It's you know, we love ophthalmologists for a good reason. Thanks. Now, what makes Sjogren's disease different from other autoimmune conditions like rheumatoid arthritis and lupus, for example, which sometimes can have overlapping symptoms, right? Not only symptoms, but overlapping features.

5:00 So I will say to start off, you know those rheumatic diseases you mentioned specifically rheumatoid arthritis, lupus and systemic sclerosis, they can be sort of sisters. So they don't have to fall into a box. Sometimes patients truly do have features of multiple diseases and and many of them truly share features with Sjogren's. To date, in those patients who have shared diseases have features of lupus and Sjogren's disease. The other disease has always predominated management because there's so little to do for Sjogren's, unfortunately, and I wish it weren't the case.

5:33 Now, what features tease out like if you have a run-of-the-mill lupus patient, run-of-the-mill Sjogren's patient, how do you tell them apart? Well, you know, Sjogren's patients are like snowflakes. Everyone's different, but a very high number of them will have profound dryness as one of their primary symptoms, which is absent in things like lupus. Others are more shared, like pain and fatigue. In addition, Sjogren's will have, again, objective extreme dryness on examination and with objective testing, and we'll also have more pronounced salivary gland involvement or exocrine gland involvement in contrast to the other diseases.

6:09 There are other features that help you tease out Sjogren's versus lupus versus systemic sclerosis, but really what makes you start thinking about Sjogren's is the symptom of dryness. And that helps you tease out from the other diseases because they all do have profound pain and fatigue, which are also symptoms of Sjogren's amongst a host of other symptoms. Because like I said, everyone is different. Right now, what actually happens inside the body in Sjogren's disease? Why do people get the classic dry eyes which I see as an ophthalmologist and dry mouth?

6:39 And what other body organs can it affect and and what symptoms or serious complications can it cause? Yeah. So let's step back again to that. What's driving this? So like I said, we do know some patients have a genetic predisposition. It's not all patients. It's just patients who have a positive blood test called an anti SSA or Rho antibody. And those patients tend to have a stronger genetic link. And what we think happens is they're, you know, they have a genetic predisposition and then a virus comes along and triggers disease and that virus causes a cell to sort of explode or apoptosis, what we say.

7:16 And the inside of the cell is now revealed to the immune system. And usually your immune system never sees the inside of a cell because it's protected by the cell membrane. But once that cell explodes, if you will, and the immune system can see the inside, now it's going to form auto antibodies. So that means that your your immune system is seeing self. It makes an antibody that usually would only make to viruses and bacteria but to self and one of those antibodies is this anti row or SSA. Now that antibody we think might be able to also Dr. inflammation.

7:48 So now you've formed antibodies and you start driving inflammation with these things called cytokines that cause a lot of local inflammation. Then unfortunately you get more cell death and cell explosion, you get more intracellular content and the cycle goes on and on. And ultimately what happens is you get immune cells, they get activated because of this inflammation. And the two immune cells that we most commonly talk about in Sjogren's are T cells and B cells. And the B cells are B for bad. The bad actor is really in Sjogren's at the end of the disease.

8:21 And they make a lot of these antibody proteins, we call it immunoglobulins. They decrease something called complement. And really them being really active is what puts us at risk for things like lymphoma, which is more common in Sjogren's. So we think this is what's going on in the gland. And ultimately we think this local inflammation causes severe dryness, but it's not so simple, right? A lot of us are still doing research into the nuances of that, but it's not just in the glands. As you mentioned, Sjogren's is a systemic autoimmune disease and so can go anywhere.

8:55 And I'll lift a few of the places it can go and it changes how we monitor patients. So lung involvement is really common and it can range from non dangerous things like a dry throat that's really bothersome and large airway disease to things called interstitial lung disease, which can increase your risk of death. The nervous system can be involved, the central nervous system like the brain can be involved. It can look a lot like multiple sclerosis and the peripheral nervous system can be involved, causing things called neuropathies.

9:26 Other organ systems can be involved. Joints are really common. You get a lot of inflammation in the joints and stiffness and pain in the joints. And that's why pain can be a hallmark of Sjogren's or one of the many reasons. And there are other organs. But really what I think a lot of patients become concerned about is this increased risk of lymphoma, which is roughly 14 fold the risk of the general population. Wow, that's. Huge. It is really big, but I do tell patients not all patients have the same risk, so there is some stratification you can do to help find out who's at higher risk and who's at lower risk.

9:58 So it it can affect many organs in the body, but like you said, the glands are most affected. That would be the salivary glands that produce your saliva. And if those glands are attacked by these B cells and the various circulating chemicals in the body, the cytokines, then those glands don't produce enough saliva and the mouth dries out. You got it, but don't forget about tears. Right. Don't forget about that, right? It also affects the lacrimal gland, which is the gland above the eyeball that produces tear fluid.

10:30 And if that gland is inflamed, it doesn't make enough tear fluid and that causes the dryness. Exactly. Who typically gets Sjogren's? Is there a typical age or gender, and how common is it? How many people have this condition? And so we do know it's very female predominant. So usually we'll say 9:00 to 1:00, but some studies all go all the way up to 20 to one female to male. Males do get it and they tend to have worse disease when they do. The peak onset is around perimenopause. Why that is, we don't know, but this makes us think that maybe hormones might be an initiating factor.

11:04 We're not sure. But there's a bimodal onset that means that there's this late onset around the time of perimenopause where most patients are diagnosed, but there's an earlier period or peak in younger women around the time of monarchy. And those younger women tend to have more severe disease. And I think finding more of those patients would be really helpful to help control their disease progress over time, especially as we get new drugs. Now, in terms of frequency, that's actually a deceptively tricky question because of how we do research.

11:36 So we usually in big studies, we use codes to find patients and then figure out how common a disease is. The problem is that Sjogren's had the same ICD code as dryness for decades, and dryness is not Sjogren's. Sjogren's is autoimmune epithelitis. It's a cause, an autoimmune disease causing inflammation in the glands. Whereas dryness can be caused by age, which all of us get, or medications or sleeping with your mouth open using AC, pap, I mean the list goes on. And so if you code dryness is the same as Sjogren's, your numbers are going to be falsely elevated.

12:14 And then there are other studies that try to be more rigorous, but then they're falsely low, I think. So most rheumatologist, Long story short, say probably around 1% of the population has Sjogren's disease, which would be just second to rheumatoid arthritis. It's pretty common. It's a lot of people. It is. Right now many people have never heard of it and like my patients when I mentioned that until they or a family member or close friend is diagnosed with this, why do you think it's still under recognized and possibly still undiagnosed based on your experience and and what you've just said?

12:47 It's probably multifactorial, right. So one, as we discussed, dryness is so common that it can be hard to recognize the disease when the presentation most of the time isn't going to be that disease. And then also I think because there have been no disease modifying therapies available, there's less drive I think to give a diagnosis. And so from a physician's or other providers perspective, you think about it less because there's less you can do about it. So I would hypothesize those two factors converge and there's probably three or four other factors that I'm just not aware of that leads to this trouble diagnosing the disease.

13:27 Right. It's a good point. If we don't have a specific treatment for it, it tends to be kind of ignored possibly. Now for many, many years we've called this Sjogren's syndrome and that's what I used to call it. And I know recently it's changed to Sjogren's disease. Why did that happen and and what does that actually mean for patients, the name change? Yeah, this was really a patient and driven initiative that we all really got behind. So syndrome sort of means a non specific constellation of symptoms with no underlying unifying pathogenic mechanism.

14:06 But Sjogren's disease is a disease, meaning that we do, we have identified clear causes for why the disease happens in the body and so it's sort of unfair to call it a syndrome. That means we don't really know what causes it. And so our Sjogren's patients felt that syndrome, not to put words in their mouth, but made it seem like a less serious process or not a targetable disease. And as we talked about, if a physician sees a process going on in a patient and there's nothing to, there's no problem pathologically, we've identified they may be less likely to treat.

14:35 And so I think it really is very important to change the name from syndrome to diagnosis because that tells you there is an abnormal, pathogenic problematic process going on in this patient's body that we need to either develop a therapy for at least recognizing clinic. And so we all voted on this. So the Children's Foundation, all patient advocacy groups across the world really worked to push this forward and we did a formalized vote and everyone agreed that this was the direction we should go to improve sort of how we manage these patients clinically.

15:07 Right. Great idea, very important. Now you mentioned a blood test, the SSA or Roe blood tests. Are there any other blood tests that are specific for this, or maybe imaging or or other kinds of things that you can do to make sure that it's really Sjogren's disease? Yeah, so we start off with questions, I think because those are the easiest before we go to tests. So, you know, if you think you're a little dry, here are 6 questions you can ask yourself. And, you know, positive answers to these would indicate you have significant dry dryness symptoms.

15:41 1 would be have you had daily persistent dry mouth for more than three months? You know, if you were to eat a saltine, would you have to take a sip of liquid to be able to swallow it, indicating again, severe oral dryness? Have you had it persistently enlarged or recurrently enlarged salivary glands? And if you haven't had it, you don't know what it is. That's good. You kind of look like a chipmunk, like mumps. Same with the eye. If you had daily persistent dry eye for more than three months, that gets a chronicity.

16:10 Do you wake up daily feeling like you have sand or grit in your eye? That gets its severity. And then asking how many times do you have to use over the counter tear substitutes and more than 3 is probably abnormal. And if you get through that screening question just because dryness is so common that you get a chronic and severity with those questions. The next step is to go to your doctor. And most doctors won't know how to measure dryness, but it's pretty easy. But they will know how to order a blood test.

16:34 And the anti SSA or raw antibody is typically the first Test we get. Around 70 to 80% of Sjogren's patients will be positive.

16:43 Now around 20 to 30% of patients are blood tests negative. And those patients unfortunately at this time need to undergo a labial salary gland biopsy, which is a tiny incision on the inside of the lip. We pluck out a few of these tiny glands. You can feel them, you have thousands, you can feel a little bumps in your lip. And then we can diagnose Sjogren's from that biopsy. We can also use ultrasound or other imaging modalities to look at the glands and we can see abnormalities. Now I will say most times the abnormalities occur in blood test positive patients.

17:12 So the SSA positive patients tend to have the abnormalities. So it doesn't always help with whether you need a lip biopsy or not. It more commonly can help like our our young patients who get disease tend not to be as dry yet we don't know why. And so those patients they're not dry, they may have a positive blood test. And the question is do you have Sjogren's or are you risk of going to have Sjogren's or are you one of the large percentage of people who just has a positive antibody but doesn't have disease, right.

17:39 That happens with many of our antibodies and the imaging can help us with that too. There are blood tests being evaluated. There's no other blood test that right now is validated and actually convincingly works to diagnose Sjogren's beside from the SSA row fifty row 6052 unfortunately. Right. What about the nonspecific inflammatory blood test like the SED rate or ESR or the Ana blood test or the CRP blood test or any of those positive in Sjogren's? Good question. So let's start off with the Ana.

18:11 So traditionally a lot of people were trained to use something called an anti nuclear antibody to screen for Sjogren's and if it was positive you would go on and get the SSA. But actually since then we've shown that the blood test we used to find an Ana doesn't work as well for anti SSA antibodies. So we don't recommend using an anti nuclear antibody as a screening test anymore. We say just go straight to that SSA, the inflammatory tests. Unfortunately they're so nonspecific, they don't help you either way.

18:40 Like if they're normal, they don't rule out Sjogren's. If they're abnormal, it could be a host of things. If they're really abnormal, it can still be a host of problems in in the rheumatic disease world. So I wish they could help more but they don't help so much with diagnosis. Right. So if there's a strong clinical suspicion of Sjogren's disease based on patients symptoms and the SSA test is negative or normal, would you then consider a biopsy just to be sure? I do recommend that in all of those patients, and I will say so 1, you know, we have the symptoms, we get the blood test, it's negative.

19:20 We make sure to do objective dryness testing. So that includes drooling stamps, drool you make in 5 minutes, It includes measuring the tears that you make and measuring if you have any damage on the surface of your eye. And if patients have any of those abnormalities, then I say, OK, you're truly very dry. It's worth it to go to a biopsy. And I'll anecdotally say, you know, one in 10 patients probably end up having Sjogren's who are severely dry. So it's much better than the general population. I feel dry odds, but most people still don't go on to have Sjogren's, and that may not have been important to sort out in the past.

19:56 But now that we're getting drugs that treat Sjogren's, it makes a difference because if you have Sjogren's, you may be eligible for certain drugs. If you don't have Sjogren's and you don't have an autoimmune cause of your dryness, giving you a drug would cause harm without any potential benefit. So I think it's worthwhile to get the biopsy if that's a question. And the last reason to get it is because there's a window of opportunity. So patients who have a lot of inflammation on their glands, they go on to get scarring and sort of wearing out of the gland.

20:24 And once that happens, you can't really diagnose Shogun's anymore because there's not any much tissue left. So if you're going to diagnose it, you need to do it sooner rather than later. And that happens on the order of like years and years and years, not so much months. But that's my justification for getting the biopsy. It's a minimally invasive procedure and it settles whether or not we should be treating you once we get therapies that would be effective. Right now you mentioned fatigue as a common symptom.

20:51 As you know the chronic fatigue syndrome and other syndrome has been around for several decades. Should patients who've been diagnosed with chronic fatigue which is non specific, get the SSA blood test? This is a difficult question because every patient presents differently, right? And so some patients really do present with fatigue as their primary symptoms. Some patients present with brain fog. Some patients present with neuropathy symptoms. I would say if you answered yes to those questions we posed, then it's probably reasonable.

21:27 You know, if you have severe recalcitrant fatigue, ask your doctor. You know, next time you're at the dentist or at the ophthalmologist, ask if you have dry eye or dry mouth. I'll say I'm a sjogrenologist. This is all I do and I have a little dry eye, but my optometrist has never asked me whether I should be concerned about Sjogren's. Now, there's probably grades to the dryness, but but you know, a lot of times dentist don't comment on it because it's just not something they're trained to do, as we talked about earlier in in this session.

21:54 So I would also ask about the exam findings. And then if you really feel you, you have those symptoms or signs, I think it's reasonable to proceed. There are other things that Sjogren's can present as, and hopefully your primary care doctor would pick that up when they saw you, right? Right now, how has Sjogren's disease been treated over the years and decades and and why has that not been optimal treatment? I think it's back to our 1800s anecdotes, so depressingly so. Right now our mainstay of therapy is symptomatic support and it's pretty what I would call algorithmic, meaning we just marched through our options step by step, starting with simple options and getting to more complex and expensive options.

22:36 And so for example, for dry mouth, we recommend, you know, using wedding agents that you can put in your mouth just to moisturize the mouth, chewing or sucking on sugar free gum or candies, and then using agents to make saliva. And that includes things like pilocarpine or sevimoline we had referenced before and they really are great making things go. And for the eyes, using, you know, preservative free over the counter eye drops is always our first step. And then I always say it's kind of like the bathtub.

23:05 But here I am preaching to the choir, choir like, you know, you want to maintain a full bathtub. You can add water to it. You can cover it to prevent evaporation, or you can make sure the drain is plugged so you're not draining out of the bathtub. And it's the same for the eye in my mind, in a simplified sort of manner, we can put in plugs to prevent draining. We can use moisture chamber eyewear to seal in the moisture or fancy get scleral lenses and we can put lots of eye drops in. Now beyond that for the eyes are many more options.

23:34 Myopia and glands or a blepharitis commonly occurs. That's inflammation of the glands that live in the eyelids. And they're really important to maintain the health of because they shouldn't be affected by Sjogren's and they make a layer of your tears. And so keeping them healthy can actually really help your eyes. And so that's eyelid hygiene like eyelid scrubs and using warm compresses on your eyes at least 10 minutes a day. And then we get to even more advanced therapies like prescription eye drops and and serum tears and we kind of go down.

24:04 That's the more esoteric algorithm that I think we get to with fewer patients. And as you mentioned, fatigue is common. Well, how do we treat fatigue? You know, unfortunately, we don't have a magic pill for it and patients are severely burdened by it. So we try to say, OK, let's see how much exercise we can do. Let's try to at least do three to five sessions of 30 minutes of exercise at whatever grade you can tolerate. And I talk a lot about ways we can do this in my clinic visit optimizing sleep.

24:32 A lot of our Sjogren's patients have really poor sleep and or unrecognized sleep apnea. So those are really treatable things that we can address to make a patient's life better. And then pain, like we have to dig into what's causing the pain. Is it joints, is it nerves? Is it a centralized process? And that's what we call nosiplastic pain when you have increased sensitivity to pain and we don't know why. So it's really quite complicated and every patient has a different mix of these symptoms and we have to structure a treatment plan based on that.

25:02 But it's largely supportive unless you have significant organ system involvement that you had referenced earlier. And then we use stronger medications off label to try to prevent severe end stage organ damage or death. So what's the role for systemic steroids, Cortisol basically or cortisone or I have some patients who are taking Plaquenil for treating Sjogren's. When do you use those medications systemically? Yeah. So we reach for Prednisone, as I said, once we start getting, once we start getting organ damage or reversible organ involvement or activity I would say.

25:42 Like lung involvement or nervous system involvement? Exactly. So lung involvement is a good example. Joints is a very common example because it tends to most patients it's more a mild pain, so we don't need to reach for steroids. But some patients come in with robust, severe joint involvement and steroids really help quiet things down. You know, with steroids we really try to use them acutely and short term and get them off because long term they have so many bad side effects. So we try to reserve it for, OK, we know this organ is getting attacked by the immune system.

26:12 We can deploy steroids in the short term to quiet it down and in the longer term, usually we use an additional therapy. One of the common ones you mentioned is hydroxychloroquine. I would say the most common place I use it for is for joint involvement to take over for steroids or in some patients I don't have to use it the steroids. I just use hydroxychloroquine to start. We can use it in a plethora of other organ system involvement. Sometimes for severe recalcitrant fatigue. I will try it, but I use sort of a diagnostic therapeutic trial.

26:44 So I asked patients to tell me what the fatigue is preventing them from doing. And then we try hydroxychloroquine for six months and we see if it's better just because fatigue can be, I, I can't put it, I don't think I can describe how severe it is in some of our patients. And so out of desperation we try because there's the risk of hydroxychloroquine is low. So we talk about something called clinical equipoise, right, the risk benefit ratio. And sometimes even though we don't think there's much of A benefit, the risk is low enough where it's worth a try.

27:13 And so sometimes I'll use it in that context. And then of course, we have stronger drugs and we can walk up that treatment ladder as the patient specifically needs. I have some patients with very severe dry eye from Sjogren's disease and the hydroxychloroquine has actually been very helpful in managing them in in some of the patients. Not everyone, but it it does help in many. So you know, it's interesting because we used to treat all patients with hydroxychloroquine and then we did a randomized control trial that ended up showing it didn't help all that much.

27:47 But in post hoc analysis, meaning when we went back and did sub analysis like in groups that we think, oh, we clinically know these patients do respond. In some of those groups we do see a response, but the trial wasn't studied to look at those like powered to look at those groups. And so now it's sort of we surmise it does help in certain populations and the ones it tends to help based on that post hoc analysis with are the ones that have a lot of that B cell activity. And a lot of those patients coincidentally will have severe epithelial damage in their eye like that the the outer lining of the eye is really, really damaged.

28:20 So, so yeah, probably a subset do improve, but we just didn't structure this study to to look at those endpoints unfortunately. Now there's exciting news about a new medication called Yanal Umab, which is made by the Novartis company that just received FDA Breakthrough Therapy designation for Sjogren's disease in January 2026, just a few months ago. Can you explain what this FDA designation means and why it's such a big deal? Yeah. So First off, I should disclose that I do consult for Novartis even though we didn't, you know, there's no payment for this specific talk.

29:01 But just so that everybody knows, I do have a conflict, but I'm happy to talk about the drug because I think it's exciting. So when you get a breakthrough designation by the FDA, one is the FDA saying there's a major clinical need for this drug? And then two, it looks like the data are strong enough that we would want to expedite moving this drug through the FDA approval process. So it's a need plus efficacy, efficacy shown by the drug and and it really I think shows promise to a quick expedite approval by the FDA and we anticipate that that will occur over the next few months.

29:35 That's, that's great. How does Yanal Yuma work differently from the current treatments? I understand has a unique dual way of targeting these nasty B cells that you mentioned of the immune system. Can you walk us through that and and kind of everyday language how the drug works? Yeah. So you know, we it targets the B cells and we talked about B cell targeting before and you know, in the past we've used other B cell targeted drugs in trials and Sjogren's, but those trials failed. And it may be because of the way this, the trial was structured.

30:07 It could have been because of who we included in the trial, or it could be because the mechanism of action or how the drug worked wasn't optimized. I will say that other B cell targeted drugs do also show some promise, but they're just in earlier phase studies or are drugs that are are close to the patent expiring. And so nobody's going to do an expensive clinical trial with them. But this drug specifically, it targets 2 mechanisms. It one depletes the B cells. So it says B cells are bad, I'm going to take you away.

30:36 OK. And that's through this antibody dependent cellular cytotoxicity long word, but cytotoxicity, toxic cytoas cell, it's toxic to cells. So it takes away the B cells. But then sometimes what happens when you take away B cells is the other cells in your body say, hey, where are my B cells? I want more. And so they make this thing called bath B cell activating factor and and that drives B cells to be made, which it seems like self defeating, right? You take away the B cells, your body says I need those B cells, I'm going to make more gives you bath and then it drives more production.

31:11 And so the second mechanism is it blocks bath receptors. So it it not only takes down the number of B cells, but it inhibits one of the ways your body makes more B cells. So it has a dual mechanism. That's why it's called Yanalimab after the God Yanis or Janis, who has two faces to remind us all that it has two ways it works. Wow, that's a very clever drug. But does it deplete the B cell so much that you're at high risk of bacterial and viral and other types of infections? That's a good question.

31:44 The clinical trial safety data look promising and they actually didn't see a lot of increased infections. They saw some low blood counts of certain types and injection site reactions. That being said, we do need B cells and our other B cell depleting drugs are associated with severe infections. And so one of the things that we don't know yet is how patients will do on these drugs long term outside the six months of the study and whether they'll be at risk for those severe infections. And we sort of assume they will be because we know that we need B cells for an intact immune system.

32:17 Right. What have the clinical trials shown so far about how well reduces symptoms like the dryness which we talked about, fatigue, joint pain, and what makes the results stand out so much that the FDA gave it this breakthrough? So I will say I work a lot with clinical trial design and thinking about how to structure these endpoints. And sometimes when trials come out, you just say, yes, no, it works. But a lot of times the way we measure these things, it's really tricky to see a signal. So I'll say they did not report dryness, pain or fatigue improving.

32:52 They they reported patient or global symptoms improving, IE patients just feeling better.

33:02 So why would patients feel better if it's not dryness, pain and fatigue? I don't know. Was it the way the questionnaire was structured? You know, does the drug really not work on the, the hallmark features of Sjogren's? Probably not. Or just the way we ask questions probably aren't good enough and we need to go back to the drawing board and ask questions in a better way. So the, the short answer to that is symptoms. We didn't really see a a strong improvement in the oral presentation. They did mention that some patients got more saliva flow, but not all.

33:34 So that was promising. And then their main primary outcome was improvement in disease activity. And so to understand what that means, you have to go back to what you asked early on, which is what organs can Sjogren's involve? And we list all these organs and we actually have 12 that we measure and we we measure disease activity in those 12 organs. Now, problem is we started off saying, what's Sjogren's? It's, you know, fatigue, pain and dryness from your glands being involved by autoimmunity. But in our disease activity index, we don't take that into account at all.

34:08 It's just not something we measure. We measure gland size, but we don't measure how dry you are. And so I think that's a major problem with how we measure disease activity in Sjogren's. But there's pluses and minuses. This is clearly very complicated. Regardless, they did see significant improvement in disease activity over 52 weeks.

34:30 So it does take some time. And then unfortunately there's a very large placebo response. So there was improvement beyond placebo of if you pool all their clinical trials of around 1.2 points. So if the disease activity ranges from zero to 123, which is what it is compared to placebo, there is a 1.2 significant change in baseline ESTAI, meaning your disease activity got better. So there is clearly a difference, but we're not 100% sure what that means clinically. And the robust placebo response really kind of effects how we interpret results because that's change over placebo.

35:08 So that again gets back to the weakness of the instruments we use to measure disease. But what was exciting is out of so many trials done for Sjogren's, this is the first clinical trial to show a significant improvement in disease activity ever or to meet its primary endpoint. It's the first trial to meet its phase three clinical trial endpoint in Sjogren's. So it was a huge deal of our conference. We're all really excited. But I will also mention at the same conference kind of from behind like that Kentucky Derby where the racehorse came from behind, you know everybody was excited.

35:40 Another B cell targeted drug put out an abstract where they met their phase three clinical trial endpoint as well. And that is also targets Bath as part of its mechanism of action, but I know a little less about that. And it was just done in China. But also, this tells us, right, we're getting promising drugs that might make disease activity better in Sjogren's. Disease activity is very important. There may be other factors that it's treating that we still don't understand because we we don't fully understand the disease as well.

36:09 You're right. And you know, one of the things that patients are really concerned about is that risk of lymphoma. And one of the questions I'll have in my mind down the road is, well, though most lymphoma is caused by those B cells being bad. And if we eliminate those B cells, do we reduce that risk? Of course, we don't know that yet, but that will be an interesting question. And another interesting question will be, can we prevent gland damage? And that gets back to the imaging question you had.

36:33 We can see abnormalities. Can we reverse those abnormalities or stop them from progressing? Those are all questions that we're going to be able to answer and are really exciting. Right. So if, if and when a drug is approved, we'll have many more patients on the drug and we'll have more data and as time goes by we'll get some of those answers. You got it. Yeah, good starting point. Was there any data on specifically on the dry eye? Do you know if these patients were were seen and tested by ophthalmologists to have tests done for that in this study or that wasn't done?

37:04 So to my knowledge, we don't have dry eye measurements. And unfortunately I think the limitation is that it's hard to get an ophthalmologist to do this thing called ocular staining score, right? I don't know if you've, but ophthalmologists are hard to get into and cornea experts are the kind that do like our staining. And so I think it can be really difficult for clinical trials to have also an ophthalmologist on site to do some of the testing. Now Shermer's anyone can do, and that's just putting strips of paper in the eye.

37:33 But I think not all rheumatologists feel comfortable doing that. Right, yeah, it's, it's a little, it can get a little tricky, but I, I'm a cornea specialist so I do the corneal staining all the time. But yeah, it's, it's difficult. It's. Tricky, right? You have to do 2 dyes. There's a timing component. It's a. Little tricky, but if you've been doing it for for many, many years on many patients, it you know, it becomes a little easier. But but it can be done. Just send your patients from Madison, WI to me, New York City.

38:01 I'll be happy to do that. I would see, I would love to. We have good cornea people, but but you know, it's so hard to get in. You guys are are popular. Yeah, yeah. Madison, WI has excellent ophthalmologist and and cornea specialist. Now, are there any severe side effects or contraindications that came up during the study or severe drug drug interactions? You know, I was surprised by how well tolerated it. Was it it really the side effect profile looked great. Like I said, I think the biggest issues were injection site reaction which happened I think in about half of patients and that's just where you inject the drug.

38:37 You get a little rash or maybe itchy. Usually those are mild, but that led to discontinuation in drug and a fair number of patients. Actually not too many, 2%, I don't mean ferrous low. And then it can cause low blood counts. So it can cause leukopenia. That means low white cells and that's a combination of your T cells and your B cells and monocytes, sort of all of your immune fighting cells, your immune system cells. And then specifically, it can cause low neutrophils, which is important because with low neutrophils we see increased risk of infection, but importantly they didn't see increased risk of infection overall.

39:14 Now again, like we said, it's a short study we'll see with long term, but the drug was really well tolerated. We anticipate based on these studies that will probably just want to monitor patients blood intermittently just to make sure those those white counts and those neutrophils don't drop too much. But other than that, I think that the monitoring will be pretty minimal for the drug. That's great. Any educated guess on when this might be approved by the FDA? How much longer a process is needed?

39:45 Well, let's see. So we, it was presented at the November ACR, that's our big rheumatology conference. And I would hazard to guess. So then the goal would be let's get this approved within a year. I mean, and it, it's, we're almost halfway there. So my guess would be in the next 6 months we probably will see the first FDA approved drug for Sjogren's. Now question will be who will it be approved for, right. So will it be people with high disease activity? Another question will be, will it, will they allow SSA positive, will they allow the SSA negative patients, the antibody negative patients to get the drug?

40:19 Most of the participants in the trial had an SSA positive. Those are all questions that we'll just have to see, you know, when, when, what the FDA says with approval metrics. Right that do you think this is a drug that'll only be prescribed by rheumatologists or eventually even internal medicine or family practice doctors might prescribe it as well, let's say if a patient is definitely SSA positive and has a classic symptoms. Yeah. You know, I don't know. Given that if past is prologue with other similar therapies typically ends up staying in rheumatology, I think most primary care physicians don't usually feel comfortable managing what we call biologic therapy that suppress the immune system.

41:05 That being said, you know, there are some places that really are care deserts, and in those places sometimes primary care does a lot more than in some bigger cities. So I think we'll have to see. But if the history of how we prescribe these things is any indicator, probably it'll be rheumatologist prescribing the drug. Yeah. Makes sense, it's a complex disease and rheumatologist have the most experience with taking care of patients with that now. Beyond this new drug, what other promising developments or research directions are you most excited about for Sjogren's patients right now?

41:41 Is there anything else on the horizon that looks promising? So many things. So research is just, so, I mean, that's what I do most with most of my time. And I think it's just there's so much innovative research happening, you know, whether it's good or bad. There are a lot of things we don't know about Sjogren's and there are a lot of people doing hard work trying to fill the gaps in what we know in terms of translating though, what we know to to treatments like new treatments. There are so many drugs in the pipeline right now for Sjogren's.

42:12 A lot of the drugs in the pipeline target those B are bad cells, but there's multiple being developed that are targeting different pathways. And I think that's really important because like I said and I've said, Oh my gosh, I'm repeating myself so much, right? Each patient has a snowflake. So why would we expect one therapy to work for all of them? I don't think that that's going to be the case. So it's imperative that we have these therapies in the pipeline that have different abnormalities that they target so we can make sure we treat all patients.

42:41 So some interesting ones that are coming. There are ones that sort of chomp away viral, let's see viral products or content because we think viruses trigger the disease and so they kind of it kind of chumps the virus that might be persisting in the body. There are some that work through the gut to adjust the immune system. There are some that target different kinds of T cells. We ignore the T cells, but they're important too. There are some local therapies so that you can, you can give to just increase saliva by injecting into sort of the ducts are are at our university.

43:17 I do a stem cell trial, so we inject stem cells into the salivary glands and seen a nice result. That's just a preliminary phase one. It's not a phase two. But what I'm trying to say is, you know, behind these two initial drugs that met their phase three clinical trial endpoint, we have almost an avalanche of drugs that are meeting their clinical trial endpoints where we never did before. So I think it's a time where there's major changes for our Sjogren's patients. I am really excited and if we get back to what you said at first, I hope that this improves our diagnosis of these patients and really recognizing the severity of this disease has and the impact on our patients quality of life.

43:57 That's great. So I want to thank you very much for coming on the Doctor Podcast program and sharing your knowledge, expertise, and experience with Sjogren's disease. We've learned a lot from you. I know I have, so we really appreciate it. I really appreciate you taking the time to talk with me today and I want to thank all of my patients and the Sjogren's Foundation for all the hard work that they do and the patients for teaching me. I really, I think lessons just about every day that I hopefully bring back to the bench to help fix their problems in addition to mine.

44:31 Thanks very much. Appreciate it. Thank you.