<p>As discussed in several presentations at <strong>ACR Convergence 2025</strong>, the basic understanding of the pathogenesis of Sjögren’s disease (SjD) is evolving. The conference also covered phase 3 trial data for ianalumab and telitacicept, 2 investigational B-cell–targeted agents that have received US Food and Drug Administration (FDA) Fast Track designation for the treatment of SjD.</p> <p><br></p> <p><em>Following these presentations, featured expert Nancy Carteron, MD, FACR, was interviewed by </em>Conference Reporter <em>Medical Director</em> <em>Lauren Weinand, MD. Clinical perspectives from Dr Carteron on these findings are presented here.</em></p>

It is now generally accepted as a working hypothesis that the pathogenesis of SjD really is one of basic immunology, from the innate immune system, which may be triggered by a virus, an autoantibody, or a toxic substance, through the adaptive immune system. That is the general framework. We have a lot more specific information on adaptive immunity with B-cell involvement, and there are multiple late-stage development programs focused on this.

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One of the sessions that covered this topic at the ACR Convergence 2025 meeting placed a little more emphasis on the T-cell aspect, with the basic science presentation on T cells by Sarah Pringle, PhD, actually focusing primarily on the oral compartment of salivary glands and acinar cells. One thing I would point out from this presentation is the basic science information highlighting the fact that the pathogenic T cells in SjD models may actually be key resident cells and not infiltrates coming from the outside, which had been the previous assumption.

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These findings can change what we think is the underlying trigger for pathogenesis, although it may not necessarily be the same in all cases. We should now begin to recognize that epithelial cells in salivary glands, depending on where they are, may present antigens to the next step in the innate immune system, which is very exciting. This is not only being studied in animal models; in fact, there are a number of groups that are actually looking at organoid cultures and even the entire acinus to identify this at different levels. So, we are going to see more of this develop out.

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There was another very interesting scientific session at ACR Convergence 2025 presented by Melissa Cunningham, MD, PhD, and Caroline Jefferies, PhD, on hormonal involvement in immune response and the differences between the sexes, as it is well recognized that SjD presents more often in women. What I was able to take away from this presentation is that, while genetics is involved, the makeup of the immune cell, particularly the T cell, can be very different when it is coming from a female vs a male host. And on top of that, there are the additional immune-modulating effects related to the differences between the hormones themselves. So, I think it is clear that the differences between the sexes are multifactorial, but further knowledge at a very basic level can add to our understanding of the heterogeneity of the disease and to our ability to manage symptoms. In addition, this session highlighted the role that obesity can play in autoimmune conditions, including SjD, because adipose tissue is proinflammatory.

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However, I think that, in terms of SjD, the big focus during the meeting was really clustered around the late-breaking abstracts on ianalumab and telitacicept, 2 investigational B-cell–targeted agents that have received FDA Fast Track designation for the treatment of SjD. Given the fact that there are no agents that are FDA approved for SjD in the United States or globally, there is significant excitement about the therapies in phase 3 trials. It is exciting to me that, as we see things move forward and hopefully actually get regulatory FDA approval for a number of different agents over the next couple of years, it will allow us to really fine-tune the pathogenesis of SjD, to better understand which subsets patients fall into, and then to better tailor the use of these agents to the individual patients we see.

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In my opinion, the therapy that people collectively think has more robust data at this point is the B-cell–targeted monoclonal antibody (mAb) ianalumab, which was discussed at ACR Convergence 2025 by Thomas Grader-Beck, MD, in a late-breaking abstract session (abstract LB24). Ianalumab is a fully human mAb that targets the B-cell receptor specifically, thereby decreasing BAFF-R levels, but it has a dual mechanism of action, also directly depleting B cells. The abstract by Dr Grader-Beck focused on a pair of global phase 3 trials, NEPTUNUS-1 and NEPTUNUS-2, and improvement in disease activity, as measured by the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI), the primary outcome measure that is used and currently accepted by regulatory agencies. These were the first phase 3 trials in SjD to meet their primary end points.

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Finally, telitacicept has a different mechanism of action, but it also targets the later stages of B-cell activation. The phase 3 study on telitacicept was presented by Lin Qiao, MD, in a poster session at the ACR meeting (poster LB11). Similar to NEPTUNUS-1 and NEPTUNUS-2, this study also had a number of study sites, but, instead of having multiple study sites across multiple countries, they were all within 1 country: China. In addition, there was not much of a placebo response in the telitacicept phase 3 trial, which is quite unusual. I am not sure how to interpret that, but I think that it is important to note.