Seronegative Sicca Syndrome: Diagnostic Considerations and Management Strategies

Area of Science:

• Rheumatology
• Immunology
• Ophthalmology

Background:

• Seronegative sicca syndrome affects patients with xerostomia/keratoconjunctivitis sicca lacking anti-SSA/SSB antibodies.
• These patients do not meet primary Sjögren's syndrome (pSS) criteria, leading to diagnostic and therapeutic challenges.
• Current antibody-centric frameworks limit understanding and classification of these diverse cases.

Purpose of the Study:

• To review the clinical, immunological, and pathological spectrum of seronegative sicca syndrome.
• To highlight diagnostic and therapeutic gaps for these unclassified patients.
• To advocate for a revised approach to sicca syndrome diagnosis and research.

Main Methods:

• Literature review of clinical, immunological, and pathological data on seronegative sicca.
• Analysis of histopathologic findings (e.g., focal lymphocytic sialadenitis).
• Examination of novel immunological markers (cytokines, autoantibodies) and clinical burden.

Main Results:

• Seronegative sicca exhibits heterogeneity, with some patients showing pSS-like histopathology and others non-immune mechanisms.
• Evidence of subclinical autoimmunity exists, indicated by elevated cytokines (BAFF, IFN-α) and novel autoantibodies (SP-1, CA-VI).
• Patients experience significant symptoms (dryness, fatigue, pain) but are often excluded from research and trials, receiving symptomatic treatment.

Conclusions:

• Seronegative sicca syndrome represents a heterogeneous group requiring broader diagnostic approaches beyond antibody status.
• Advanced immunophenotyping and inclusion in research are crucial for understanding disease evolution and developing targeted therapies.
• A paradigm shift is needed to embrace the full spectrum of sicca syndromes, improving care for all affected individuals.