Background/Purpose: Sarcoidosis, a multisystem inflammatory disorder of unknown etiology, exhibits diverse clinical manifestations, with symptomatic musculoskeletal involvement being relatively uncommon but potentially debilitating. We conducted a comprehensive investigation into the transcriptomic profiles of muscle biopsies obtained from patients diagnosed with sarcoid myopathy across various international cohorts.

Methods: RNA sequencing was performed on muscle biopsies collected from 37 patients diagnosed with sarcoid myopathy. Comparative analysis included a total of 669 samples, comprising myositis patients, disease controls, and healthy individuals. Differential expression and pathway analyses were utilized to discern distinctive transcriptomic signatures specifically linked to muscle sarcoidosis.

Results: Muscle biopsies from patients with sarcoid myopathy exhibited distinct molecular signatures. Alongside elevated expression of conventional macrophage markers (CD14, CD68), notable features included elevated levels of IFNG, IFNG receptors, and type 2 IFN-inducible genes, with a modest increase in type 1 IFN genes or type 1 IFN-inducible genes. T cell markers (CD3, CD4, CD8) were also upregulated, alongside increased immunoglobulin expression and pronounced elevation of type 1 and type 2 HLA molecules. Muscle regeneration markers showed intermediate levels, with a predominant decrease in type 1 muscle fiber markers (MYH7) compared to type 2 muscle fiber markers (MYH1, MYH2). Elevated interleukin levels (including but not restricted to IL1, IL6, and IL8) further characterized the inflammatory milieu.

A distinct set of genes associated with hyperactivated macrophages effectively distinguished sarcoid myopathy from other myositis and correlated with disease activity at a transcriptomic level. Notably, genes such as CHIT1, FPB1, LYZ, and MMP12 exhibited over 16-fold elevation compared to other myositis types (all q-values < 1e-61).
Metagenomic investigations did not identify candidate sequences of infectious agents potentially linked to this condition.

Conclusion: Sarcoid myopathy exhibits a distinctive array of transcriptomic markers linked to hyperactivated macrophages that are correlated with disease activity. Subsequent studies are crucial for elucidating the precise mechanisms driving this immune dysregulation and may pave the way for targeted therapeutic interventions aimed at modulating macrophage activity in this condition.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/specific-transcriptomic-profile-associated-with-disease-activity-in-muscle-biopsies-from-patients-with-sarcoid-myopathy/