Background/Purpose: Esophageal involvement in patients with systemic sclerosis (SSc) is common, but tissue-specific pathological mechanisms are poorly understood. Esophageal muscle atrophy without concomitant fibrosis is found in the majority of SSc patient autopsy specimens. We hypothesized that detailed characterization of SSc esophageal histopathology and molecular signatures at the level of gene expression would provide insights into SSc esophageal disease pathogenesis.

Methods: Esophageal biopsies were prospectively obtained during esophagogastroduodenoscopy (EGD) in 16 clinically well-characterized SSc patients and 7 subjects without SSc. Upper and lower esophageal biopsies were evaluated for histopathology and gene expression by DNA microarray.  Biopsies were scored for basal cell hyperplasia, lymphocyte infiltration, and degree of collagen deposition. The presence of a hiatal hernia and/or esophagitis on gross examination of the esophageal lumen at the time of EGD was considered evidence for esophagitis. Transcripts with the most similar expression between an individual’s upper and lower biopsies, but most different expression between individuals, termed ‘intrinsic genes,’ were identified and hierarchically clustered to define molecular subsets (FDR <1.1%). Consensus clustering and SigClust formally confirmed the number of significant clusters within the cohort. Significance Analysis of Microarrays (SAM) identified differentially expressed transcripts between subsets, and g:Profiler identified functional terms enriched in subsets.

Results: Upper and lower esophageal biopsies showed nearly identical patterns of gene expression within an individual. Three groups of patients with SSc were identified molecularly: an inflammatory group (upregulated genes related to immune processes), a proliferative group (upregulated genes indicative of proliferating cells), and a non-inflammatory group (downregulated immune genes). The inflammatory signature was independent of esophagitis as assessed by basal cell hyperplasia grade, infiltrating lymphocyte counts, and presence of gross esophagitis/hiatal hernia indicating immune cell activation may underlie the inflammatory esophageal gene expression signature. Inflammatory patients tended to have more collagen deposition than patients in the combined non-inflammatory/proliferative, but the results were not statistically significant (p = 0.38). Molecular classification of esophageal biopsies was independent of SSc subtype (p=0.62), serum autoantibodies (p=0.23) and esophagitis (p=1.00).

Conclusion: Similar to skin, Inflammatory and Proliferative Intrinsic Subsets are present SSc patients’ esophagi suggesting that molecular subsets are a global feature of SSc end target organ pathology. SSc esophageal molecular subsets are distinct from subtypes identified clinically.  Inflammation rather than fibrosis was the most dominant gene expression signature in SSc esophageal biopsies.  The inflammatory signature is observed in biopsies that lack large inflammatory infiltrates suggesting that immune activation is a major driver of SSc esophageal pathogenesis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/molecular-characterization-of-systemic-sclerosis-esophageal-pathology-identifies-inflammatory-and-proliferative-signatures-with-few-fibrotic-markers/