Session Title: Sjogren's Syndrome I: Clinical Perspectives
Session Type: Abstract Submissions (ACR)
Sjögren’s syndrome (SS) is a chronic autoimmune disease which targets exocrine glands, particularly salivary and lacrimal glands. While all SS patients have abnormal secretory function and inflammatory infiltration of their salivary glands, there is significant heterogeneity in terms of disease features, pathology and clinical course. Elucidating the inflammatory pathways which are active in pathologic tissues has important implications for defining disease subsets and monitoring disease activity. With the increasing availability of therapies which target specific immune pathways, defining the activity of distinct molecular pathways in target tissues will be important for selecting therapy. The type I and type II IFNs, which are implicated in SS pathogenesis, are particularly relevant in this regard.
Clinical data and a frozen labial salivary gland was obtained from each of 82 participants enrolled in the Sjögren’s International Collaborative Clinical Alliance registry (NIH/NIDCR contract HHSN26S201300057C) with the following characteristics: (i) 53 individuals meeting ACR criteria for primary SS; (ii) 29 age and sex-matched controls lacking serologic and pathologic evidence of SS, of which 14 exhibited evidence of dry eye disease (OSS ≥3 for either eye). Protein lysates were generated from SS and control labial salivary glands, proteins were separated by SDS-PAGE and immunoblotted with specific markers of type I or type II IFN activity. Protein expression was normalized to the level of a loading control within the same sample and subject to hierarchical clustering to define patterns of IFN activity (high vs low). Correlations between IFN activity and categorical SS phenotypic features were analyzed using Fisher’s exact test. Continuous phenotypic characteristics were compared between groups using a Wilcoxon rank sum test.
IFN activity was low or absent in controls and detected at high levels in 31 of 53 (59%) SS patients. While patterns consistent with type I-predominant (n=9), type II-predominant (n=11) and mixed I/II (n=11) IFN activity were evident, these patients were indistinguishable in regards to key SS phenotypic features, except focus score which was highest in type II-predominant patients (p=0.024). Stratification of SS patients by high vs low IFN activity revealed associations of high IFN activity with high titer ANA (p=0.0016) and SSA (p=0.0161) antibodies, hyperglobulinemia (IgG ≥1445 mg/dl, p=0.0005; IgA ≥400 mg/dl, p=0.0335) and higher focus scores (p<0.0001). Additionally IFN high patients demonstrated greater evidence of glandular dysfunction as determined by a decreased ability to produce saliva (UWS; 0.164 vs 0.549 ml/5min, p=0.0003) and tears (Schirmer; 4 vs 6.5 mm/5min, p=0.0368).
Our data indicate that the parent phenotype in SS (chronic exocrine gland dysfunction, inflammatory infiltration and autoimmunity) includes distinct molecular subtypes, segregated by magnitude and pattern of IFN responses. While the resulting disease subtypes are clinically similar, therapies targeting type I and/or type II IFN may need to be selected based on prior analyses of which specific IFN pathway(s) are active in vivo in individual patients.
J. C. Hall,
A. N. Baer,
M. Y. Lam,
L. A. Criswell,
L. Casciola Rosen,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/molecular-diagnostics-for-patient-subsetting-in-sjogrens-syndrome/