Symptom-Based Cluster Analysis Categorizes Sjögren's Disease Subtypes: An International Cohort Study Highlighting Disease Severity and Treatment Discordance.

OBJECTIVE: Although symptom relief is a critical aspect for successful drug development in Sjögren's disease, patient experiences with Sjögren's-related symptoms are understudied. Our objective was to determine how pain, dryness, and fatigue, the cardinal symptoms of Sjögren's disease, drive cluster phenotypes. METHODS: We used data from the Sjögren's International Collaborative Clinical Alliance (SICCA) Registry and a Sjögren's Foundation survey. We performed hierarchical clustering of symptoms by levels of dryness, fatigue, and pain. Using international and US cohorts, we performed multiple logistic regression analysis to compare the clusters, which included comparisons of differences in symptoms, quality of life (QoL), medication use, and systemic manifestations. RESULTS: Four similar clusters were identified among 1,454 SICCA registrants and 2,920 Sjögren's Foundation survey participants: 1) low symptom burden in all categories (LSB); 2) dry with low pain and low fatigue (DLP); 3) dry with high pain and low to moderate fatigue (DHP); and 4) high symptom burden in all categories (HSB). Distribution of SICCA registrants matching the symptom profile for each cluster was 10% in the LSB cluster, 30% in the DLP cluster, 23% in the DHP cluster, and 37% in the HSB cluster. Distribution of survey participants matching the symptom profile for each cluster was 23% in the LSB cluster, 14% in the DLP cluster, 21% in the DHP cluster, and 42% in the HSB cluster. Individuals in the HSB cluster had more total symptoms and lower QoL but lower disease severity than those in the other clusters. Despite having milder disease as measured by laboratory tests and organ involvement, individuals in the HSB cluster received immunomodulatory treatment most often. CONCLUSION: We identified 4 symptom-based Sjögren's clusters and showed that symptom burden and immunomodulatory medication use do not correlate with Sjögren's end-organ or laboratory abnormalities. Findings highlight a discordance between objective measures and treatments and offer updates to proposed symptom-based clustering approaches.

Elevating serotonin pre-partum alters the Holstein dairy cow hepatic adaptation to lactation.

Serotonin is known to regulate energy and calcium homeostasis in several mammalian species. The objective of this study was to determine if pre-partum infusions of 5-hydroxytryptophan (5-HTP), the immediate precursor to serotonin synthesis, could modulate energy homeostasis at the level of the hepatocyte in post-partum Holstein and Jersey dairy cows. Twelve multiparous Holstein cows and twelve multiparous Jersey cows were intravenously infused daily for approximately 7 d pre-partum with either saline or 1 mg/kg bodyweight of 5-HTP. Blood was collected for 14 d post-partum and on d30 post-partum. Liver biopsies were taken on d1 and d7 post-partum. There were no changes in the circulating concentrations of glucose, insulin, glucagon, non-esterified fatty acids, or urea nitrogen in response to treatment, although there were decreased beta-hydroxybutyrate concentrations with 5-HTP treatment around d6 to d10 post-partum, particularly in Jersey cows. Cows infused with 5-HTP had increased hepatic serotonin content and increased mRNA expression of the serotonin 2B receptor on d1 and d7 post-partum. Minimal changes were seen in the hepatic mRNA expression of various gluconeogenic enzymes. There were no changes in the mRNA expression profile of cell-cycle progression marker cyclin-dependent kinase 4 or apoptotic marker caspase 3, although proliferating cell nuclear antigen expression tended to be increased in Holstein cows infused with 5-HTP on d1 post-partum. Immunofluorescence assays showed an increased number of CASP3- and Ki67-positive cells in Holstein cows infused with 5-HTP on d1 post-partum. Given the elevated hepatic serotonin content and increased mRNA abundance of 5HTR2B, 5-HTP infusions may be stimulating an autocrine-paracrine adaptation to lactation in the Holstein cow liver.