Breakthrough Biologics: Charting the Course for Sjögren's Syndrome Treatment in 2024

Sicca complex, characterized by dry eyes and mouth, is distinct from primary Sjögren's syndrome (pSS), which is associated with keratoconjunctivitis sicca and xerostomia as part of a broader autoimmune disease affecting multiple organs. This distinction is essential for accurate diagnosis and treatment planning, as pSS can significantly impact a patient's quality of life. It is important to note that pSS affects not only exocrine glands but also vital organs such as the lungs, kidneys, and blood cells. Currently, there is no gold standard treatment or universally effective drug for pSS, as various immune pathways and mechanisms are implicated in its progression, not all of which are directly associated with disease advancement. A multicenter retrospective cohort study showed that comorbidities such as male sex, older age, interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), high European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI), thrombocytopenia, anemia, high IgA level, and glucocorticoid treatment instead of pSS related organ damage, were the main causes of death in Chinese patients. And hydroxychloroquine (HCQ) use might improve the long-term survival observed 2. Research from Taiwan's National Health Insurance Research Database highlighted that patients diagnosed with SLE at least 1 year after being diagnosed with primary Sjögren's syndrome were identified as cases. HCQ has been used to treat patients with pSS and has shown potential in delaying the onset of SLE; however, its use in pSS patients appears to correlate with a lower likelihood of developing SLE in the future 3. As of 2023, numerous clinical trials have been conducted to explore potential treatments for Sjögren's syndrome. Unfortunately, several clinical drug trials targeting pathways such as interferon (IFN), tumor necrosis factor (TNF) inhibitors, interleukin (IL)-1 receptor antagonists, IL-6 receptor inhibitors, and anti-ICOSL antibodies have either failed or been terminated. However, monoclonal antibodies targeting B-cell activating factor (BAFF), CD20, CD38, and IL-2 show promise, indicating that longer and larger sample trials may be necessary to achieve success 4. For that reason, we have compiled a list of ongoing or completed clinical trials. The European Alliance of Associations for Rheumatology 2024 congress brought exciting updates on several clinical trials for Sjögren's syndrome (SjS) treatments, offering hope for patients with this challenging autoimmune disease. Nipocalimab, an anti-neonatal Fc receptor monoclonal antibody, showed significant promise in the Phase 2 DAHLIAS study. The 15 mg/kg dose group demonstrated a statistically significant improvement in the primary endpoint of ClinESSDAI score at 24 weeks compared to placebo (p = 0.002). Patients receiving this dose experienced over 70% relative average improvement in the primary endpoint. Secondary endpoints, including organ assessments and physician evaluations, also showed clinically meaningful improvements 5. Iscalimab, an anti-CD40 monoclonal antibody, continued to show positive results in its Phase 2b dose-ranging trial. At 48 weeks, all iscalimab doses demonstrated further improvements in ESSDAI, unstimulated salivary flow rate, and patient-reported outcomes. These improvements were maintained in patients who continued iscalimab treatment and improved in those who switched from placebo 6. Dazodalibep, another promising agent, met its primary endpoint in both patient groups (systemic disease and severe symptomatology) at Day 169 in its Phase 2 trial. Amgen reported the first findings showing dazodalibep improved major biomarkers in Sjögren's disease 7. Ianalumab, a BAFF-targeting antibody, is currently in Phase 3 trials and shows promise for becoming one of the first licensed treatments for Sjögren's disease. The 52-week safety and efficacy data indicated that the 300 mg dose group continued to provide clinical benefits 8. However, not all trials yielded positive results. These developments represent significant progress in the search for effective Sjögren's syndrome treatments. The positive results from nipocalimab, iscalimab, dazodalibep, and ianalumab trials offer hope for patients who currently have limited treatment options. As research continues, these emerging therapies may lead to a paradigm shift in treating the underlying processes of Sjögren's syndrome, potentially improving the quality of life for millions of patients worldwide (Table 1). In summary, it is important to focus on the ongoing clinical trials and the need for new drugs targeting autoantibodies in Sjögren's syndrome. The increasing number of clinical trials across various medical fields highlights the urgency of addressing this condition. Continued research is vital to improve treatment options and ultimately enhance the quality of life for those affected by this challenging autoimmune disease. T.-C.H. drafted the manuscript. J.C.-C.W. critically revised the manuscript. Both authors approved the final version of the manuscript. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.