Pamidronate-induced Clinical Remission in Chronic Non-bacterial Osteomyelitis is Associated with Reduced Vg9Vd2 T-cell Receptor Expression

Objective: Chronic non-bacterial osteomyelitis (CNO) is an under-recognised, clinically significant disorder of sterile bone inflammation. The underlying aetiology is unknown, which has hampered development of novel diagnostics and treatments. Treatment with pamidronate (a bisphosphonate) reduces symptom flares in many patients, but it is unclear how it specifically modulates CNO pathology. We therefore sought to elicit potential pathogenic pathways in CNO by transcriptome analysis pre- and post- pamidronate treatment. Methods: Clinical data and peripheral blood were collected from children with CNO immediately before and 3-5 months after their first cycle of pamidronate treatment. Participants had not previously received immunomodulatory treatment. RNA-sequencing was undertaken on peripheral blood, followed by differential gene expression analysis and Gene Set Enrichment Analysis. Results: Six children (median age 8 years, range 5-12) with CNO who demonstrated clinical improvement post-pamidronate (mean change in pain at rest visual analogue scale = -4.3) were included in the study. Two genes were identified with significantly reduced expression in post-pamidronate samples relative to pre-pamidronate: i) TRDV2 (log2 fold-change -3.5, FDR<0.001); and ii) TRGV9 (log2 fold-change -1.8, FDR<0.003), encoding two biologically linked sub-units of the gamma delta T-cell receptor (TCR). Pathway analysis revealed suppression of multiple pathways post-treatment, including osteoclast differentiation (FDR<0.05) and Th17 cell differentiation (FDR<0.05). Conclusions: We identify a possible role of Vg9Vd2 T cells in CNO pathogenesis. More broadly, we demonstrate that peripheral blood may yield information relevant to CNO pathogenesis. These findings should be validated in a larger longitudinal cohort, alongside assessment of Vg9Vd2 TCR expression and functional studies.