(1) Background: The aim of this study was to analyze labial minor salivary gland biopsy (
MSGB) findings of a large sicca cohort and to examine their associations with
Sjogren's syndrome (SS)-associated
laboratory markers, phenotypic characteristics and systemic manifestations. Moreover, we sought to explore the ability of
MSGB to identify SS patients among subjects with pre-diagnosed
fibromyalgia (FM). (2) Methods: Included were all patients of three rheumatology departments having undergone a diagnostic
MSGB within 9 years. Next to the examination of histological and immunohistochemical findings, we focused on activity and chronicity parameters of the underlying disease,
autoantibodies, presence of systemic and hematologic involvement, as well as
chronic pain and SS comorbidities. (3) Results: Among the 678 included patients, 306 (45.1%) had a positive focus score (FS). The remaining patients (n = 372) served as control subjects. There were significant correlations between FS and
hypergammaglobulinemia (p < 0.001), ANA and
rheumatoid factor positivity (both; p < 0.001), a weak significant correlation with erythrocyte sedimentation rate (rho = 0.235; p < 0.001) and a negative correlation with
nicotine use (p = 0.002). Within the primary SS subgroup, FS was associated significantly with glandular enlargement (p = 0.007) and systemic hematologic manifestations (p = 0.002). Next to FS, CD20 cell staining showed an excellent diagnostic performance in the diagnosis of SS by an area under the curve of 0.822 (95%CI 0.780-0.864; p < 0.001). Interestingly, 42.1% of all patients with
fibromyalgia (FM) having received an
MSGB could be diagnosed with SS. (4) Conclusion: By examining one of the largest cohorts in the literature, we could show that
MSGB histological and immunohistochemical findings not only play a key role in the classification and diagnosis of SS but could also provide important information regarding SS phenotype and systemic manifestations. Furthermore,
MSGB may help differentiate patients with FM from patients with subclinical SS who suffer primarily from
chronic pain.