Seronegative Sicca Syndrome: Diagnostic Considerations and Management Strategies
Seronegative sicca syndrome encompasses patients who present with xerostomia and/or keratoconjunctivitis sicca but lack anti-SSA/SSB antibodies and do not fulfill current classification criteria for primary Sjögren’s syndrome (pSS). Despite symptom overlap with pSS, these individuals remain diagnost...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-06-01
|
| Series: | Life |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2075-1729/15/6/966 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849705129985441792 |
|---|---|
| author | Yordanka M. Basheva-Kraeva Krasimir I. Kraev Petar A. Uchikov Maria I. Kraeva Bozhidar K. Hristov Nina St. Stoyanova Vesela T. Mitkova-Hristova Borislav Ivanov Stanislav S. Karamitev Nina Koleva Aleksandar Marinkov Veselin A. Vassilev |
| author_facet | Yordanka M. Basheva-Kraeva Krasimir I. Kraev Petar A. Uchikov Maria I. Kraeva Bozhidar K. Hristov Nina St. Stoyanova Vesela T. Mitkova-Hristova Borislav Ivanov Stanislav S. Karamitev Nina Koleva Aleksandar Marinkov Veselin A. Vassilev |
| author_sort | Yordanka M. Basheva-Kraeva |
| collection | DOAJ |
| description | Seronegative sicca syndrome encompasses patients who present with xerostomia and/or keratoconjunctivitis sicca but lack anti-SSA/SSB antibodies and do not fulfill current classification criteria for primary Sjögren’s syndrome (pSS). Despite symptom overlap with pSS, these individuals remain diagnostically and therapeutically unclassified. This review studies the clinical, immunological, and pathological spectrum of seronegative sicca, highlighting its heterogeneity and the limitations of antibody-centric diagnostic frameworks. Histopathologic findings in some seronegative patients—including focal lymphocytic sialadenitis—mirror those seen in pSS, suggesting underlying immune-mediated glandular damage. In others, nonspecific or normal biopsy findings suggest non-immune mechanisms. New evidence of immune activity, such as elevated cytokines (BAFF, IFN-α), and novel autoantibodies (SP-1, CA-VI), further supports the concept of subclinical autoimmunity in a subset of these patients. Clinically, they often face significant burden, including dryness, fatigue, and pain, yet remain excluded from most research cohorts, therapeutic trials, and clinical guidelines. Their management is often individualized, relying on symptomatic therapies rather than immunomodulatory agents. The lack of validated diagnostic criteria and prognostic markers compounds the uncertainty surrounding disease evolution, as some patients may later seroconvert or develop systemic features. To address these gaps, a paradigm shift is needed—one that embraces the spectrum of sicca syndromes, incorporates advanced immunophenotyping, and allows inclusion of seronegative patients in research and care algorithms. |
| format | Article |
| id | doaj-art-c27e05e4c8ac43ffb2ba9cb7ed7a425b |
| institution | DOAJ |
| issn | 2075-1729 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Life |
| spelling | doaj-art-c27e05e4c8ac43ffb2ba9cb7ed7a425b2025-08-20T03:16:33ZengMDPI AGLife2075-17292025-06-0115696610.3390/life15060966Seronegative Sicca Syndrome: Diagnostic Considerations and Management StrategiesYordanka M. Basheva-Kraeva0Krasimir I. Kraev1Petar A. Uchikov2Maria I. Kraeva3Bozhidar K. Hristov4Nina St. Stoyanova5Vesela T. Mitkova-Hristova6Borislav Ivanov7Stanislav S. Karamitev8Nina Koleva9Aleksandar Marinkov10Veselin A. Vassilev11Department of Ophthalmology, Faculty of Medicine, Medical University of Plovdiv, 4002 Plovdiv, BulgariaDepartment of Propedeutics of Internal Diseases, Medical Faculty, Medical University of Plovdiv, 4002 Plovdiv, BulgariaDepartment of Special Surgery, Medical Faculty, Medical University of Plovdiv, 4002 Plovdiv, BulgariaDepartment of Otorhinolaryngology, Medical Faculty, Medical University of Plovdiv, 4002 Plovdiv, BulgariaSecond Department of Internal Diseases, Section “Gastroenterology”, Medical Faculty, Medical University of Plovdiv, 4002 Plovdiv, BulgariaDepartment of Ophthalmology, Faculty of Medicine, Medical University of Plovdiv, 4002 Plovdiv, BulgariaDepartment of Ophthalmology, Faculty of Medicine, Medical University of Plovdiv, 4002 Plovdiv, BulgariaFaculty of Medicine, Medical University of Plovdiv, 4002 Plovdiv, BulgariaDepartment of Orthopedics and Traumatology, Faculty of Medicine, Medical University of Plovdiv, 4002 Plovdiv, BulgariaSpeciality “Assistant Pharmacist”, Medical College, Medical University of Plovdiv, 4002 Plovdiv, BulgariaDepartment of Propedeutics of Internal Diseases, Medical Faculty, Medical University of Plovdiv, 4002 Plovdiv, BulgariaDepartment of Physiology, Medical Faculty, Medical University of Plovdiv, 4002 Plovdiv, BulgariaSeronegative sicca syndrome encompasses patients who present with xerostomia and/or keratoconjunctivitis sicca but lack anti-SSA/SSB antibodies and do not fulfill current classification criteria for primary Sjögren’s syndrome (pSS). Despite symptom overlap with pSS, these individuals remain diagnostically and therapeutically unclassified. This review studies the clinical, immunological, and pathological spectrum of seronegative sicca, highlighting its heterogeneity and the limitations of antibody-centric diagnostic frameworks. Histopathologic findings in some seronegative patients—including focal lymphocytic sialadenitis—mirror those seen in pSS, suggesting underlying immune-mediated glandular damage. In others, nonspecific or normal biopsy findings suggest non-immune mechanisms. New evidence of immune activity, such as elevated cytokines (BAFF, IFN-α), and novel autoantibodies (SP-1, CA-VI), further supports the concept of subclinical autoimmunity in a subset of these patients. Clinically, they often face significant burden, including dryness, fatigue, and pain, yet remain excluded from most research cohorts, therapeutic trials, and clinical guidelines. Their management is often individualized, relying on symptomatic therapies rather than immunomodulatory agents. The lack of validated diagnostic criteria and prognostic markers compounds the uncertainty surrounding disease evolution, as some patients may later seroconvert or develop systemic features. To address these gaps, a paradigm shift is needed—one that embraces the spectrum of sicca syndromes, incorporates advanced immunophenotyping, and allows inclusion of seronegative patients in research and care algorithms.https://www.mdpi.com/2075-1729/15/6/966seronegative sicca syndromeprimary Sjögren’s syndromeautoimmune exocrinopathy |
| spellingShingle | Yordanka M. Basheva-Kraeva Krasimir I. Kraev Petar A. Uchikov Maria I. Kraeva Bozhidar K. Hristov Nina St. Stoyanova Vesela T. Mitkova-Hristova Borislav Ivanov Stanislav S. Karamitev Nina Koleva Aleksandar Marinkov Veselin A. Vassilev Seronegative Sicca Syndrome: Diagnostic Considerations and Management Strategies Life seronegative sicca syndrome primary Sjögren’s syndrome autoimmune exocrinopathy |
| title | Seronegative Sicca Syndrome: Diagnostic Considerations and Management Strategies |
| title_full | Seronegative Sicca Syndrome: Diagnostic Considerations and Management Strategies |
| title_fullStr | Seronegative Sicca Syndrome: Diagnostic Considerations and Management Strategies |
| title_full_unstemmed | Seronegative Sicca Syndrome: Diagnostic Considerations and Management Strategies |
| title_short | Seronegative Sicca Syndrome: Diagnostic Considerations and Management Strategies |
| title_sort | seronegative sicca syndrome diagnostic considerations and management strategies |
| topic | seronegative sicca syndrome primary Sjögren’s syndrome autoimmune exocrinopathy |
| url | https://www.mdpi.com/2075-1729/15/6/966 |
| work_keys_str_mv | AT yordankambashevakraeva seronegativesiccasyndromediagnosticconsiderationsandmanagementstrategies AT krasimirikraev seronegativesiccasyndromediagnosticconsiderationsandmanagementstrategies AT petarauchikov seronegativesiccasyndromediagnosticconsiderationsandmanagementstrategies AT mariaikraeva seronegativesiccasyndromediagnosticconsiderationsandmanagementstrategies AT bozhidarkhristov seronegativesiccasyndromediagnosticconsiderationsandmanagementstrategies AT ninaststoyanova seronegativesiccasyndromediagnosticconsiderationsandmanagementstrategies AT veselatmitkovahristova seronegativesiccasyndromediagnosticconsiderationsandmanagementstrategies AT borislavivanov seronegativesiccasyndromediagnosticconsiderationsandmanagementstrategies AT stanislavskaramitev seronegativesiccasyndromediagnosticconsiderationsandmanagementstrategies AT ninakoleva seronegativesiccasyndromediagnosticconsiderationsandmanagementstrategies AT aleksandarmarinkov seronegativesiccasyndromediagnosticconsiderationsandmanagementstrategies AT veselinavassilev seronegativesiccasyndromediagnosticconsiderationsandmanagementstrategies |