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Primary Sjogren's Syndrome Associated with Lung Adenocarcinoma: Probing the Potential Common Pathogenic Mechanisms and Experimental Verification
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From Molecular Pathophysiology to Clinical Trial Design in Sjögren's Disease: A Three-Axis Framework

Muhammad Soyfoo1, Julie Sarrand1, Christine Delporte2

  • 1Department of Rheumatology, Hôpital Erasme, Université Libre de Bruxelles (ULB), Route de Lennik 808, 1070 Brussels, Belgium.

International Journal of Molecular Sciences
|July 15, 2026
PubMed

Insights

Sjögren

Area of Science:

  • Immunology
  • Rheumatology
  • Precision Medicine

Background:

  • Sjögren's disease (SjD) lacks approved disease-modifying therapies despite extensive research.
  • Past clinical trials have yielded limited success, potentially due to overlooking SjD's biological heterogeneity.
  • Existing therapeutic strategies may be misaligned with the diverse pathogenic mechanisms within SjD.

Purpose of the Study:

  • To propose a novel framework for classifying Sjögren's disease based on dominant biological axes.
  • To align trial designs and therapeutic strategies with specific SjD endotypes for improved outcomes.
  • To reframe Sjögren's disease research towards a precision medicine approach.

Main Methods:

  • Development of a tripartite framework organizing SjD into interferon-driven, B-cell/lymphoproliferative, and symptom/fibro-structural axes.
  • Identification of characteristic biomarkers, histopathology, and prognostic features for each axis.
  • Analysis of recent clinical trial designs and outcomes in relation to patient stratification.

Main Results:

  • Recent trials employing phenotype-defined cohorts and targeted therapies show promising clinical benefits.
  • Examples include positive results for ianalumab, iscalimab, nipocalimab, and dazodalibep in specific SjD subpopulations.
  • Stratification aligned with biological axes enhances the detectability of meaningful clinical benefit.

Conclusions:

  • Sjögren's disease may not be intrinsically treatment-resistant but rather treatment-mistargeted.
  • A precision medicine approach, integrating molecular endotypes and phenotype-matched therapies, is crucial for SjD.
  • The proposed tripartite framework offers a model for advancing therapeutic development in heterogeneous autoimmune diseases.
Keywords:
B-cell hyperactivityCXCL13Sjögren’s diseasebiomarkersclinical trial designianalumabinterferon signaturepatient stratificationprecision medicinetranslational rheumatology

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