| Emerging Targeted Therapies for Sjögren’s Disease and Evolving Clinical-Trial Endpoints |
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Kyung-Ann Lee |
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Division of Rheumatology, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul, Korea |
| 쇼그렌병의 최신 표적 치료와 임상시험 설계의 변화 |
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이경언 |
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순천향대학교 부속 서울병원 관절류마티스내과 |
Correspondence:
Kyung-Ann Lee, Tel: +82-2-710-3063, Fax: +82-2-709-9554, Email: 107144@schmc.ac.kr
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Received: 26 January 2026 • Revised: 20 April 2026 • Accepted: 12 May 2026 |
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| Abstract |
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Sjögren’s disease (SjD) is a systemic autoimmune disorder characterized by glandular dysfunction and diverse extraglandular manifestations. Despite a strong immunological rationale, many immunomodulatory trials have failed to show consistent efficacy, largely due to clinical heterogeneity and limitations of conventional outcome measures. Growing evidence indicates a dissociation between systemic inflammatory activity and patient-reported symptom burden, leading to recent trials stratifying patients into systemic activitydominant and symptom-dominant phenotypes and aligning primary endpoints accordingly. The European Alliance of Associations for Rheumatology (EULAR) Sjögren’s Syndrome Disease Activity Index (ESSDAI) remains a key endpoint for systemic disease activity; however, it is affected by intrinsic variability and regression to the mean, contributing to high placebo responses. The EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) captures core symptoms but demonstrates limited sensitivity to change and weak correlations with objective glandular function. To address these limitations, composite response measures, such as Composite of Relevant Endpoints for Sjögren's Syndrome (CRESS) and Sjögren's Tool for Assessing Response (STAR), have been developed to integrate systemic activity, symptoms, glandular function, and serologic markers. Recent phase 2 randomized controlled trials have demonstrated this paradigm shift. Inhibition of the CD40-CD40L pathway with dazodalibep and iscalimab showed efficacy when phenotype-appropriate endpoints were applied. B-celldirected therapies, including B-cell activating factor (BAFF) receptor blockade with ianalumab and BAFF/A Proliferation Inducing Ligand dual inhibition with telitacicept, have demonstrated improvements in systemic activity with supportive biomarker changes. Remibrutinib, an oral Bruton's tyrosine kinase (BTK) inhibitor, improves systemic disease activity; however, symptom-based endpoints remain a challenge. Neonatal Fc receptor (FcRn) blockade with nipocalimab reduced clinical disease activity in seropositive high-activity subgroups without consistent symptom improvement. Overall, effective therapeutic development for SjD requires mechanism-informed patient stratification and endpoint strategies that link biological activity to clinically meaningful outcomes. |
| Key Words:
Sjögren’s disease; Sjögren’s syndrome; Therapy; Clinical trial; Stratification |
| 주제어:
쇼그렌병; 쇼그렌증후군; 치료; 임상시험; 환자군 층화 |
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