Chapters Transcript Targeting B Cells as Therapeutic Agents to Modify Sjögren's Disease Course: NYU Langone Seminar in Advanced Rheumatology Thank you Pam and uh thank the organizers for inviting me to make the trip back uh from Long Island uh this morning and as Pam said we're gonna shift a little bit more uh into the B cell and the uh clinical realm uh and uh addressing uh whether there may be some therapies, uh, on the horizon. Uh, for Sjogren's, uh, and, um, might these involve a B cells, so I don't have to tell this audience, uh, that Sjogren's is a fairly prevalent disorder and among our non, uh, rheumatologic colleagues, uh, maybe, uh, still, uh, somewhat, uh, undiagnosed, uh, lack of treatment for Sjogren's, uh, can result in uh uh severe. Outcomes, uh, in the glandular, the, uh, tissue supplied by the glandular areas, particularly, uh, loss of vision, uh, and, uh, loss of uh dentition leading to poor uh nutrition and poor outcomes, uh, depending on criteria used and populations, uh, the range of extragraial manifestations is wide but can reach 80% and in our experience. Uh, with our cohort, the patients who have Sjogren's more than 15 years have extra glandular manifestations that range in the 60 to 80% uh range and of course, uh, one of the uh challenges in managing these patients over a long. Period of time is the risk uh for B cell lymphoma further uh focusing our efforts perhaps on B cells uh nonetheless, uh, the therapeutic landscape unfortunately, uh, is, uh, not robust uh there. On the uh positive side there is a lot of interest uh now uh among rheumatologists, ophthalmologists, uh, oral biology specialists and pharmaceutical companies in developing uh effective therapies, uh, for Sjogren's syndrome yet. Uh, other than the drugs that can promote secretions like Pylocarpinene and sveyle, there is still no FDA approved a unique, uh, treatment, uh, for Sjogren's syndrome. Uh, part of the problem in, uh, studying, uh, therapies and Sjogren's syndrome. Uh, is that the disease, uh, like many of our diseases, uh, is, uh, heterogeneous, and, um, we all know, uh, that there's a subset, uh, that, uh, is zero negative, uh, that, uh, tends to be a little bit more difficult to diagnose because you, uh, still. Uh, need, uh, tissue, uh, whereas on the other hand, uh, the zero positive patients as we know is marked, uh, generally, uh, by high levels of Roland law and has an association, uh, with the MHC mainly HLA uh DQ alpha one. Uh, DR3, uh, family of genes, uh, our European colleagues, uh, for using a cohort of approximately 600, um, patients, um, looked at, uh, various clinical. Uh, subset, uh, using, uh, hierarchical, uh, clusters, uh, and found and divided them into, uh, subsets with low symptom burden, high symptom burden, uh, something known as a dryness dominant, uh, subset with fatigue and a pain dominant subset, uh, with fatigue. Uh, they then, uh, took this paradigm and applied it to two published but negative clinical trials, the, uh, Joeer trial, uh, that looked at hydroxychloroquine and Shogren's and the tractti trial, uh, which was another negative trial of rituximab and Shogren's. And found actually uh that there was an association with some of these uh clinical subsets, um, interestingly, the high symptom burden subset uh in post hoc analysis uh showed, uh. In effect for hydroxychloroquine, uh, whereas this dryness dominant subset with fatigue and, uh, again a post hoc analysis of the tract this data, uh, showed an effect for rituximab. however, uh, these clinical subsets while interesting and perhaps a useful, uh, correlate poorly. Um, with, uh, transcriptomic, uh, and other, uh, biological measures, uh, of the disease. Uh, nonetheless, uh, the group in Spain, um, as published here by, um. Uh, Brita Zeron, um, working, uh, with, uh, Mao, uh, Ramos, uh, and colleagues, uh, in a systematic review of literature, uh, showed that moderate to high risk, uh, for severe disease, uh. Correlated with the degree of B cell activity uh as measured by Roan Law, seropositivity, uh, the presence of rheumatoid factor, then hypocomplementemia, cryolobual anemia, and the appearance of monoclonal, uh, proteins. So, um, there's been a lot of attention recently focused on the B cell, uh, in Sjogren's and despite the fact, uh, that the key uh tissue lesion of Sjogren's focal lymphocytic yiditis or FLS is a T cell predominant lesion. Uh, and also has a preponderance of CD4 cells, uh, in the lesion. Uh, there are regions in the lacrimo and salivary gland, uh, where there are, uh, plentiful B cells as we know they're associated, uh, with germinal, uh, centers. Uh, they, uh, produce, uh, the characteristic antibodies of the disease, uh. Engagement of CD40 as we'll uh talk a little bit about later uh promotes class switching and higher affinity antibodies and there have been publications, uh, correlating uh R and row and law, um, positivity with certain extra glandular manifestations, particularly, uh, the skin lesions which, as you know, resent. Symbols of acute cutaneous lupus and almost all Sjogren's associated lymphomas are B cell derived uh marginal zone lymphomas in the node and their counterpart malt, uh, mucosal associated lymphomas, um, in the glandular tissue and occasionally in the GI tract and in the lung. As I mentioned, one of the positive um developments over the last several years has been the interest in developing. Uh, therapies, uh, and modern therapies, uh, for Sjogren's disease, and this slide just shows some of, uh, the, uh, potential, uh, therapeutic targets and some of the agents that have been trialed, uh, in Sjogren's and the box. Uh, focuses on the therapies that are focused on B cell, uh, activity in Sjogren, so we've seen and I'll show you some of the data on, um, on BAF receptors, um, anti-bath. Uh, anti-CD20, of course, uh, BTK inhibitors and co-stimulatory, uh, inhibitors, uh, such as, uh, anti CD40. So there have been 3 general approaches in inhibiting B cell function in Sjogren's. Uh, one is, uh, obviously depletion as we know from uh rituximab. however, as I'll also show you, uh, there's an anti-bath receptor antibody, uh, that also has B cell depleting properties. Uh, another approach has been to block B cell, uh, proliferation. Uh, and this can involve, uh, Brutons, Tyrazine kinase, uh, inhibitors, uh, as well as growth factor, uh, stimulator inhibitors such as, uh, BAF inhibitors, and then there have been approaches toward blocking, uh, co-stimulation you heard, uh, just, uh, very elegantly from Doctor, uh, way and. Um, about, uh, PD1, uh, PDL one, and she mentioned, uh, CTLA 4. Um, and there have been, uh, studies on abatacept, uh, in Sjogren's that, um, haven't been, uh, terribly, uh, positive, uh, but there have been some newer studies involving inhibition of, uh, CD40 on the B cell, uh, which prevents interaction with, uh, CD-40 ligan. Uh, on the T helper cell, uh, which, uh, appeared to show signals, um, in terms of inhibiting Sjogren's, uh, activity, this is the first study, uh, that showed some type of signal, uh, for CD20 blockade, uh, in the treatment of, uh, Shogren's and, uh, Carrubi at all, uh, Italy. Um, compared a cohort of patients, uh, treated with rituximab to another cohort of patients treated, uh, for Sjogren's syndrome with oral demarts, uh, primarily methotrexate, uh, and, um. Uh, Eiran And this showed a positive result looking at uh the SI end point which is the European Sjogren's syndrome Disease Activity Index which we talk about. Uh, again, in, in, in terms of end points, unfortunately this study wasn't controlled, uh, for the use of IV methylprednisolone, the 100 mg of Solu-Medrol that is usually co-administered, uh, with rituximab so that, um, its results, uh, really were called into question and that was followed by a randomized control trial in Europe, uh, led by, um, Valerie. Uh, Dasha Pensek and Xavier Maritz's, um, group, uh, in France, uh, and they look in the study tears they administered 1 g of rituximab at week 0 and 2. And uh looked at end points at 24 weeks and these end points were largely PROs uh greater than 2 or 4, in terms of a global response pain uh fatigue and dryness, and they measured as uh. Uh, uh, uh, multi-organ disease activity index as a secondary endpoint and you could see this study, um, absolutely, uh, showed no effect, uh, it failed and caused a lot of deflation, uh, in the Sjogren's community, uh, regarding, uh, the emergence of a new therapy. However, um, clinical experience, uh, and other studies did suggest that, uh, B cell depletion, uh, might be, uh, still, uh, a way forward, uh, in Sjogren's and, and this is anecdotal, but this is just one of our patients who actually. Had recurrent disfiguring uh massive swelling who became resistant uh to short pulses of corticosteroids was treated with rituximab and had prolonged 6 to 12 month uh remission in salivary gland swelling, which was a, uh, finding that was was seen, uh, clinically. Uh, in many Shogren centers. Why, um, did tears fail so miserably? Well, certain things plague, uh, Sjogren's clinical trials. Uh, there can be an excessive reliance, uh, on PROs, uh, where, um, this is a very heterogeneous uh disease. Uh, there may be an underemphasis on biologically relevant outcomes, uh, such as, uh, biomarkers and things like salivary gland ultrasound scores. Um, in tears, the outcome measure reporting scale was in millimeters in terms of the PRO and going for instance from 60 to 30 milers requires a 50% improvement. In other words, the attainment, say the equivalent of an ACR 50. The outcome measure reporting interval in the tract, another negative study was 6 months after the last dose, and as we Bruce and I were talking this morning, that's just about when you would give the second, uh, dose of rituximab. The SDe has a mean range of 0 to 123 maximum points. The meanest dye in tears was 10. Was it just too low a threshold to detect change? And uh the definition and assessment of musculoskeletal pain in these trials is rather diffuse it may represent other entities such as fibromyalgia or osteoarthritis in this age group and again the rituximab regimen. Uh, sometimes doesn't take into account B cell repopulation kinetics. So fortunately we're beginning to see a change in our outcome measures and we're moving from just um visual analog scale, uh, and the SD. Uh, to more composite, uh, indices similar to the ACR 2050 DAS 28 that incorporate measures that are sensitive to change and we're gonna begin to see in Sjogren's, uh, trials that are using Crest, uh, which is a. Composite of relative endpoints in Sjogren's syndrome and Sjogren's tool for assessment response uh that uh do incorporate, um, some of these elements and the first application of this type of outcome measure that has responsive elements uh was. utilized in a post hoc analysis of tears and this was Divy Kornek of the French group and they looked for 30% improvement of two or 5 measures that actually showed response uh in other clinical trials and these included oral dryness. Uh, VAS ocular dryness, fatigue, unstimulated hole, salivary flow, and the sed rate, and by applying this SSRI 30 they did see significant responses with rituximab in tears. And as we know from all the studies by the late Pierre Unanu, um, B cells will repopulate in the gland, um, after 4 months of, uh, treatment, uh, we see some here at 12 months, certainly at 24 months. Uh, these, uh, tend to be antigen selected mature B cells, but moreover. Treatment with rituximab results in a dramatic increase in B cell activating factor in bath, uh, in the serum, and this could play a role in increased proliferation and repopulation. Of B cells, uh, so would BAF inhibition be effective? There's actually one published trial. It's an open label trial. Uh, I won't go into too much detail the time with it, but it did show a signal. But the next published trial looking at bilimumab was a combination trial of bilimumab and rituximab and Shogren's published by Xavier Marriott, uh, two years ago. Uh, this was 4 arms, uh, placebo, rituximab and biliumab, uh, the bilimumab, uh, being started at week 0. Uh, to week 24 and the rituximab given at week 8 and week 10 versus the single drugs alone. And this showed superior depletion. It's the yellow line, uh, with the combination superior suppression of IGG whether or not that's a good thing, um, reduction in memory B cells, uh, and uh rheumatoid factor and that's in the blood in the gland. Uh, the combination was superior in B cell depletion at week 24. Did it have an effect clinically? Well. It seemed that the SI, which is this composite measure of 12, uh, domains, uh, did respond, uh, and, uh, salivary flow tended to increase, uh, by week 24 in the combination group. One caution. these were trends and these, these were not statistically significant, uh, in a robust, uh, manner. So another approach using uh looking at BAF uh has been utilized and that's the drug ionalimab um which is currently in trial which it has a dual effect uh it blocks bath function but due to ADCC and some uh effects of CDC complement uh activity, it is a depleting antibody. And this was studied in a phase two trial um and it did uh demonstrate a a superior reduction uh in SI at the highest dose of 300 mg. Uh, however, this was not a robust, um, decrease, but the trend. Um, was statistically significant, uh, and, uh, I will show you some data on, um, conversion, uh, from low, um, and high, uh, disease activity, um. Segments and you can see that um the 300 mg dose um reduced the proportion of patients with high disease activity from 33% to 2% um while uh increasing uh salivary flow decreasing, uh, IGG so um we're awaiting a phase three trial. Um, with this drug, uh, other approaches to B cell inhibition involve co-stimulation, uh, and, uh, the data I'll show you focuses, uh, on here on the left on CD40 inhibition. Um, The drug Escalimab is currently in phase two trials. It's an anti CD4 antibody. If you look at the the last um bullet, you'll see that one of the concerns of this drug was induction of thromboembolic events. Because earlier studies on CD4 inhibition and lupus, many of us may remember, uh, activated, uh, bound to FC receptors on monocytes, platelets, and cause thrombosis. This has an inert FC tail, uh, an earlier phase twoA study in 44 subjects at the higher dose, uh, showed uh a reduction, um. In SI this is the higher dose, uh, cohort, uh, as well as improvement in, uh, visual analog scales and, uh, fatigue, uh, indices. Um, we all probably remember Bruton's Tyrazine kinase from medical school. Uh, it's inhibition will, uh, it's mutation, certain mutations will block the progression of pro B cells to pre- B cells, and, uh, in that sense clinically results in X-length, uh, a gamma globulin anemia. Uh, however, um, Bruton's thyroxine kinase inhibitors are being explored experimentally for several diseases, uh, hematologic diseases, but including Sjogren's, uh. Where in B cells it can inhibit proliferation and there also is BTK in myeloid cells and monocytes where it's inhibition can reduce uh innate cytokine production. And this is a drug called Remirutinib, and it's um been studied in a phase two trial in Sjogren's and this does have statistically significant effects on SI. Uh, as well as salivary flow rates and several relevant biological parameters including CXCL 13 which tends to correlate with germinal center production which, uh, in some studies associates with risk uh for development of lymphoma and finally. Um, I wanna mention, uh, a drug that involves, uh, antibody, uh, recycling, uh, antibodies against, uh, the neonatal FC receptor, the FCRN, uh, nippocalumab, uh, is a drug that can bind to this, um, protective receptor which, as we know, um. We most of us know well, uh, from its existence on the placental, uh, sensitial uh trophoblast where it facilitates uh transfer of maternal, uh, IGG to afford protection of the feet. This, uh, however, this is present on many other cells including epithelial cells and can result in the recirculation and long half life of antibodies including autoantibodies. So if you block it. And that's what this antibody nippocalumab does it blocks FCRN so it can't protect these IGG molecules leads to their degradation, uh, in lysosomes, uh, and is studied intensely in multiple sclerosis. I don't have the data, but, uh, Johnson and Johnson just released, um. Information 3 weeks ago uh that a phase 2 study in Sjogren's reached its end point. So in summary, although T cells are the dominant population in Sjogren's, uh, focal lymphocytic cyloitis lesions, B cells are present in substantial number and correlate with disease activity. Uh, clinical experience and post hoc analysis of rituximab data suggests the signal for efficacy in Shogren's and, uh, the Shogren's, uh, foundation guidelines group, um, which I'm involved with, uh, did in. 2017 2018 published in arthritis care and research a recommendation that rituximab may be considered uh for patients with moderate to severe Sjogren's and extra glandular manifestations. I have the reference if you need it. Uh, dual B cell directed inhibition with rituximab and biliumab appears safe and effective and inhibits salivary gland B cell repopulation at 24 weeks. A BAF receptor blockade with ironalimab displayed an 89% responder rate. In a 2B trial CD40 inhibition with the scalimab resulted in an SI response in a phase two trial and nipacalumab and FCRN, uh, monoclonal antibody, as well as Remiruinib, a BTK inhibitor or an early clinical development. Uh, thanks. That is what. Mhm Hi Doctor Carson. Hi, um, somewhat, uh, I guess corollary or tangential question, comment question, and that is that, um, often in Sjogren's patients we observe that a lot of them also have antibodies for other autoimmune diseases, uh, Hashimoto's, primary biliary cholangitis, etc. um, so, uh, the question is, have you observed that phenomenon in your Sjogren's cohort? And does the existence of other autoantibodies or overlapping autoimmune diseases, uh, portend a better response to B cell lucky? Yeah, yeah, that's, um, very good point. Uh, so yes, um, there's ample literature on transition of what was called primary Sjogren's syndrome to lupus. In our cohort, approximately 29% of our patients initially diagnosed with Sjogren's and looked at retrospectively have 4 criteria, uh, for lupus, uh, you know, we know about the overlap with uh rheumatoid arthritis and sika. Uh, so called secondary Shogrens which we don't like to use anymore, we tend to call them overlaps, and there are, uh, several reports of the subset of Shogrens with centromere, uh, antibodies, uh, that may exhibit some vascular. Uh, manifestations and uh scleroderma like manifestations and yeah, uh, one of the reasons we don't like the term secondary Sjogren's is because people tend to think of it as Sjogren's associated with the major connective tissue diseases such as lupus, rheumatoid arthritis and sclera. Derma, but there's even potentially more overlap with organ specific autoimmunity such as, as you mentioned, autoimmune thyroid disease, um, subclinical uh pancreatic disease, uh, multiple sclerosis, etc. etc. Right, yes, that was very that was a wonderful talk. I really, uh, learned a lot. Uh, I, I two quick questions. I think you sort of talked around it, but is it a problem, uh, in Sjogren's patients, uh, with the use of rituximab alone of early B cell repopulation compared to RA? And the other question I had was. Uh, with the current, uh, success of the anti-FCRM therapy, are you starting to think about Sjogren's as a primary autoantibody directed or mediated disease? Yeah, two great questions. Uh, yeah, I mean, I think, you know, in part it depends on the regimen. Uh, and the retreatment, you know, in terms of rituximab, you know, vis a vis, uh, the bath, or, you know, where the concomitant corticosteroids or other DMAs are used and may be suppressing, you know, the bath, uh, to a certain extent, but no, I think that that is, that's certainly especially the the dual study seemed to point to that as an issue. And yeah, I mean, I one of the areas I I didn't have time to go into um was the um anti muscarinic. Uh, antibody, you know, the anti-M3 or, uh, antibodies that have been detected by Tom Gordon and, and others and, and perhaps, um, aquaporins and, you know, perhaps, uh, some cross reactivity with anti, uh, with the M5, uh receptor that has come out in certain transcriptomic, uh, studies so. You know, I always, when I, you know, talk about Sjogren's more, uh, sort of globally, I, I always talk about it is, is actually teach it to our, they pushed me to teach it to our first year medical students in the Long Island Medical school and I was very resist. I said they don't need to know about Sjogren's syndrome, but once they pushed me to that's all you have to talk about Sjogren's all right. So once they pushed me to do it, I, I said this is very important rationalizing because it's really a combination of an organ specific immu autoimmune disease and a systemic autoimmune disease. So I, I think there's that antibody mediated it's become the central paradigm, right? Yeah, exactly. Doctor Carson, thank you for the great talk. I had a question. I, I follow about 12 young women with high tide or SSA, no symptoms, maybe a little non-specific arthralgia, but, uh, IGG level around 5000, and in my mind these are pre-clinical primary Sjogren's patients, um. You know, my thought, my expectation is that there might be a window and we may get the best bang for our buck with early B cell directed therapy, almost abortive before we're seeing glandular involvement. I was just wondering if you had any opinion on how you approached these patients. Yeah, that's, uh, those are always a challenge, um, yes, we, I mean, in my experience we tend to see higher levels of total ser IgG and Sjogren's than perhaps any other, uh, rheumatic disease, you know, certainly more than rheumatoid arthritis and in many cases of lupuscyte that just speaks to. You know, the, the strong polyclonal, uh, B cell activation and early, uh, phases of the, uh, disease. Um, yeah, I mean this would be a great population to study with, let's say a B cell, uh, agent, uh, to see if, if it, and, and they're, you know, it's similar to the, uh, Abatas study that was recently published in, uh, early, uh, pre-clinical rheumatoid arthritis, um, you know, could this be? I had also. I, I, I think a great thing to study would be whether to treat with a B cell blocking agent would prevent the development of lymphoma, and I always felt that you, you know, needed, uh, an investigator that had a lot of longevity to do that study. Uh, however, unfortunately one of the patients that we had treated, uh, with rituximab for massive, uh, salivary gland enlargement, uh, recently succumbed to a gastric, uh, lymphoma, so it's, it's not gonna be perfect. Thank you. Hi, thank you so much for that informative talk. Um, could you comment at all about whether retuximat has helped in autonomic dysfunction and if not how you treat that? And the second question is, is there any utility in using this new early Sjogren's panel that's commercially available for your zero negatives? OK, two great questions, um, yeah. What was the first I'm focusing on the dysfunction, yeah, yeah, yeah, yeah, that's, uh, so we're stay tuned because, um, our, uh, foundation guidelines group is currently, uh, doing our systematic review meta-analysis, uh, and consensus. Uh, expert panel of vote on management of peripheral neuropathy and Sjogren's and hopefully that'll be published, uh, shortly, but we, uh, do have neurology experts, uh, in our group, particularly autonomic uh experts so that's a very um. It's emerging to be a very important the overlap with pots, uh, very important, um, aspect of, uh, Sjogren's, uh, and you know we're approach it seems like it's going to be approached with pharmacologic, uh, miedrine and you know, other, um, uh, drugs, uh, that target. Uh, the autonomic nervous system and, you know, possibly IVIG. Um, but you know, yeah, that is, that's emerging to be a very important, uh, area, uh, in, uh, Sjogren's as to this show test, I think you're referring to. Uh, it's interesting we have a group called Shownet. It's sort of a national group of Shogren's people that get together on a Friday afternoon, uh, organized beautifully by Sarah McCoy at the University of Wisconsin, and we just heard a presentation on alternate antibodies and anyone coming to the NYU Grossman Journal Club Thursday morning, I'm gonna present. Uh, a journal club article on other, uh, novel, uh, antibodies, but to date the sensitivity and specificity is, is just not there. OK, thank you. Published March 14, 2024 Created by Related Presenters Steven Carsons, MD View full profile
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