Marked parotid enlargement is seen in this 15-year-old girl with Sjögren’s disease of three-year duration.
BARCELONA, SPAIN—In recent years, such organizations as the Sjögren’s Foundation, EULAR and ACR have switched from using the term Sjögren’s syndrome to Sjögren’s disease. The reason for this change is to recognize that Sjögren’s is not just a constellation of symptoms but, rather, represents a distinct disease entity that should be recognized as such. At EULAR 2025, Gaetane Nocturne, MD, PhD, professor in the rheumatology department of Paris-Saclay University, Paris, France, followed this trend in her talk titled, Sjögren’s Disease: What Is New.
Dr. Nocturne began the lecture discussing how epithelial dysfunction is a hallmark feature of Sjögren’s disease and how findings related to a premature aging phenotype in resident salivary gland stem cells (SGSC) have shed light on the disease’s pathogenesis.
In a paper by Pringle and colleagues, the authors found that SGSC in primary Sjögren’s disease exhibits features of premature aging, including reduced numbers of cells, impaired ability for self-renewal, diminished capacity for differentiation and evidence of cellular senescence. Based on these findings, the authors speculated that current disease-modifying antirheumatic drugs (DMARDs) are unlikely to restore glandular function and that regenerative approaches, such as supplementation with healthy SGSCs, may be necessary to recover saliva production in patients with the disease.1
Dr. Nocturne also discussed a paper by Meudec and colleagues that demonstrated a link between interferon and epithelial dysfunction in patients with Sjögren’s disease by showing that salivary gland organoids maintain a persistent interferon signature and exhibit impaired epithelial function compared to controls. In this same study, the authors found that treatment with tofacitinib, a Janus kinase (JAK) inhibitor that blocks interferon signaling, improved the swelling response in differentiated salivary gland organoids from patients with Sjögren’s disease (for context, swelling capacity in response to cholinergic stimulation is a functional marker of epithelial secretory activity).2 These findings suggest that interferon may play a larger role in the pathogenesis of Sjögren’s disease than was previously appreciated, and this may have implications for selecting the best therapeutic targets.
According to Dr. Nocturne, several early steps explain the pathogenesis of Sjögren’s disease. First, there are triggers like interferon stimulation via mitochondrial RNA that target the epithelium. Next, activation of tissue-resident memory T cells leads to the specific targeting of acinar cells because of cytotoxicity. Following this, there is activation of pericytes, which are perivascular stromal cells that play a critical role in maintaining microvascular stability, regulating endothelial function, and modulating tissue fibrosis. There is then immune cell recruitment in the form of B cells and T cells and, finally, there is the formation of organized, ectopic lymphoid aggregates within the salivary glands (termed tertiary lymphoid structures) as a result of the chronic inflammation that has occurred.
Although the end result of this process may be similar across patients, Sjögren’s disease is regarded as a heterogeneous condition with a wide range of clinical manifestations. Such diversity among patients, Dr. Nocturne explained, can make the disease difficult to treat and to study. Thus, the work from Tarn and colleagues on stratifying patients with Sjögren’s disease into different clinically and biologically distinct subgroups based on patient-reported symptoms has been of great help.
Interferon may play a larger role in the pathogenesis of Sjögren’s disease than was previously appreciated. This may have implications for selecting the best therapeutic targets.
In a study of more than 600 patients with primary Sjögren’s disease, patients were separated into four groups: 1) low symptom burden, 2) high symptom burden, 3) dryness dominant with fatigue, and 4) pain dominant with fatigue. The authors found that these subgroups show significant differences in immunological markers, peripheral blood lymphocyte counts, autoantibody status, and transcriptomic profiles. Of great interest to clinicians is the finding that reanalysis of trial data stratifying patients into these subgroups suggested that there may be a positive treatment effect with hydroxychloroquine in the high-symptom-burden group and of rituximab in the dryness dominant with fatigue group.3
Given that there are no U.S. Food & Drug Administration (FDA) approved treatments for Sjögren’s disease and selection of therapy for patients remains a challenge, Dr. Nocturne believes that more work should be done to stratify patients in order to predict potential response to specific treatments.
It is on the subject of treatment that things seem to be evolving in the field of Sjögren’s disease of late. Dr. Nocturne provided an overview of several positive phase 2 clinical trials taking place in this space.
The first study was on dazodalibep, a CD40 ligand antagonist. In this study, two populations of patients with Sjögren’s disease were studied: one with moderate-to-severe systemic disease activity and another with high symptom burden but limited systemic involvement. In this study, dazodalibep was found to significantly improve disease activity and patient-reported outcomes compared with placebo at day 169 in both groups. The medication was generally well tolerated, with adverse events including COVID-19, diarrhea, headache, and infections.4
The next study was of iscalimab, a monoclonal antibody targeting CD40. The study involved two cohorts of patients with Sjögren’s disease: 1) a dose-ranging cohort of patients with a EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) score of 5 or higher and a EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) score of 5 or higher who were randomly assigned to subcutaneous iscalimab 150 mg, 300 mg, 600 mg or placebo in a 1:1:1:1 fashion and 2) a proof-of-concept cohort of patients with an ESSDAI score of less than 5, ESSPRI (dryness or fatigue) score of 5 or higher, and Impact of Dry Eye on Everyday Life score of 30 or higher who were randomly assigned to iscalimab 600 mg or placebo in a 1:1 fashion.
In the first cohort, iscalimab at 150 mg and 600 mg subcutaneously every two weeks significantly reduced disease activity (ESSDAI) at 24 weeks compared with placebo. In the second cohort, iscalimab 600 mg showed a trend toward improvement in patient-reported symptoms (ESSPRI), though this was not statistically significant.5
Taken together, these studies have created a great deal of excitement around the CD40 pathway.
In a study from Dorner and colleagues evaluating remibrutinib, a selective oral Bruton’s tyrosine kinase (BTK) inhibitor, patients with moderate-to-severe Sjögren’s disease who met 2016 ACR/EULAR criteria and were anti-Ro/SSA positive were randomized to receive remibrutinib 100 mg once or twice daily or placebo for 24 weeks. At 24 weeks, remibrutinib significantly improved ESSDAI scores compared to placebo, though it did not significantly affect patient-reported symptom scores in the form of ESSPRI. There was also a trend toward improved unstimulated salivary flow, and the medication was found to be well tolerated, with a favorable safety profile and significant changes in blood gene expression and serum protein profiles.6
In a separate study from Dorner and colleagues investigating ianalumab, a monoclonal antibody against B-Cell Activating Factor (BAFF) Receptor (BAFF-R), patients were randomized to receive 5, 50 or 300 mg of the medication subcutaneously every four weeks. Sustained efficacy was observed with 300 mg dosing, as demonstrated by improvements in ESSDAI, patient- and physician-reported outcomes, and stimulated salivary flow rates. Autoantibody levels also showed numerical improvement. Of note, there were three cases of grade 3 neutropenia that occurred post-treatment.7
Dr. Nocturne’s talk created a buzz for a disease that is getting a lot of buzz. Time will tell in seeing which treatments pan out, but it is clear that Sjögren’s has entered the public consciousness in a way that it did not in the past.
Jason Liebowitz, MD, FACR, is an assistant professor of medicine in the Division of Rheumatology at Columbia University Vagelos College of Physicians and Surgeons, New York.
References
- Pringle S, Wang X, Verstappen GMPJ, et al. Salivary gland stem cells age prematurely in primary Sjögren’s syndrome. Arthritis Rheumatol. 2019 Jan;71(1):133–142.
- Meudec L, Goudarzi N, Silva-Saffar SE, et al. Development of salivary gland organoids derived from patient biopsies: A functional model of Sjögren’s disease. Ann Rheum Dis. 2025 Jul;84(7):1195–1206.
- Tarn JR, Howard-Tripp N, Lendrem DW, et al. Symptom-based stratification of patients with primary Sjögren’s syndrome: Multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials. Lancet Rheumatol. 2019 Oct;1(2):e85–e94.
- St Clair EW, Baer AN, Ng WF, et al. CD40 ligand antagonist dazodalibep in Sjögren’s disease: A randomized, double-blinded, placebo-controlled, phase 2 trial. Nat Med. 2024 Jun;30(6):1583–1592.
- Fisher BA, Mariette X, Papas A, et al. Safety and efficacy of subcutaneous iscalimab (CFZ533) in two distinct populations of patients with Sjögren’s disease (TWINSS): Week 24 results of a randomised, double-blind, placebo-controlled, phase 2b dose-ranging study. Lancet. 2024 Aug 10;404(10452):540–553.
- Dörner T, Kaul M, Szántó A, et al. Efficacy and safety of remibrutinib, a selective potent oral BTK inhibitor, in Sjögren’s syndrome: Results from a randomised, double-blind, placebo-controlled phase 2 trial. Ann Rheum Dis. 2024 Feb 15;83(3):360–371.
- Dörner T, Bowman SJ, Fox R, et al. Safety and efficacy of ianalumab in patients with Sjögren’s disease: 52-week results from a randomized, placebo-controlled, phase 2b dose-ranging study. Arthritis Rheumatol. 2025 May;77(5):560–570.
