Unmasking Patient Subtypes in Sjögren’s Disease to Enable Personalized Care

Sjögren’s disease is a heterogenous autoimmune disorder marked by dryness, fatigue, and systemic complications. But heterogeneity is no longer just a clinical inconvenience that contributes to diagnostic and therapeutic inertia; it’s now also a path to precision care.

Based on a recent review published in the International Journal of Molecular Sciences, recent stratification efforts are beginning to decode patient subtypes with molecular and clinical fidelity, raising the possibility of tailored therapy and early intervention before irreversible tissue damage occurs.

Here’s an in-depth summary of the key takeaways.

IFN Signatures Redraw the Immunologic Map

Across multiple cohorts, interferon (IFN) gene expression has emerged as a dominant molecular signal in over half of patients with Sjogren’s disease.

Notably, whole blood transcriptome data reveal that high IFN-α activity correlates with anti-SSA/Ro, anti-SSB/La, and rheumatoid factor positivity as well as systemic disease burden. Distinct IFN subtypes, like type I, II, and mixed, can be detected in salivary gland biopsies, with type II being associated with more aggressive pathology.

These findings position IFN pathways not just as diagnostic markers but as therapeutic targets. Agents modulating JAK/STAT, HDAC, PI3K, and IFNAR signaling are now under investigation, supported by evidence that IFN-high patients may derive the greatest benefit from immunomodulatory strategies.

Symptom-Based Clustering: Beyond Glandular Involvement

Patient-reported outcomes, particularly dryness, pain, and fatigue, remain pivotal in stratifying disease phenotypes. Current tools like the Newcastle Sjögren’s Stratification Tool and cluster analyses from UK, Korean, and U.S. cohorts consistently identify up to four subtypes, ranging from low symptom burden to high symptom burden, dryness-dominant, and pain-dominant phenotypes.

Interestingly, these symptom-defined clusters often show distinct molecular profiles. For instance, the dryness-dominant with fatigue subtype exhibits high IFN activity, B-cell hyperactivity, and biomarkers like CXCL13, which is a chemokine linked to salivary gland pathology and lymphoma risk.

These biomarkers may not only define clinical subtypes, but also forecast complications like lymphoproliferative disease.

Discordance Between Symptoms and Systemic Activity

Molecular clustering reveals a complex interplay between symptoms and systemic disease.

For example, although the B-cell active/low symptom burden cluster shares IFN and autoantibody features with more symptomatic clusters, it manifests clinically as mild. Conversely, the high systemic activity cluster overlaps symptomatically with high symptom burden clusters, but it displays distinct cytokine and chemokine signatures.

This discordance underscores the limitations of symptom-only stratification and affirms the need for molecular diagnostics in both clinical trials and routine care.

Multimodal Omics Define Endotypes and Inactive States

Multi-omics approaches, including transcriptomic, proteomic, and methylomic profiling, have delineated consistent clusters across independent cohorts. Key themes include:

• IFN-driven clusters, often with severe phenotypes and systemic inflammation
• Lymphoid-enriched clusters, showing milder but chronic immune activation
• Inflammatory/myeloid clusters, which are linked to elevated IL-6, IL-10, and STAT3, with high ESSDAI scores
• "Healthy-like" clusters, possibly representing remission or subclinical states, often indistinguishable from controls in omics data

These molecular endotypes may soon inform eligibility for clinical trials, guide therapy selection, and refine disease monitoring frameworks.

Working Toward Disease-Modifying Therapies

Based on recent data, the case for molecularly guided treatment is no longer theoretical. Re-analyses of the JOQUER and TRACTISS trials show that response to hydroxychloroquine and rituximab varies meaningfully across symptom-defined clusters and that biomarkers, like CXCL13, IL-22, and IFN-inducible chemokines, further stratify responders. This underscores the importance of precise patient selection.

Clinical Takeaway

Sjögren’s disease is not one condition, but several biologically and clinically distinct syndromes masquerading under a shared name. Clustering by symptoms alone is a start, but integrating molecular profiling provides the depth required for personalized care.

The next decade in Sjogren’s disease care will hinge on our ability to operationalize these insights into real-world workflows, bridging stratification science with actionable immunotherapy.

Reference:
Pecorelli L, Klein K. Insights into Patient Heterogeneity in Sjögren’s Disease. International Journal of Molecular Sciences. 2025; 26(13):6367. https://doi.org/10.3390/ijms26136367