- Indian Rheumatology association
Ramya Janardana DNB, MD, Fellowship in Rheumatology
Professor, Department of Clinical immunology and Rheumatology, St John’s Hospital, Bengaluru, Karnataka
This study seeks to identify heterogeneity of fibroblast like synoviocytes (FLS) in the context of relapse vs remission in rheumatoid arthritis (RA). The molecular techniques used were single cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) on synovial tissues of RA patients.
Despite the current standard of care 30-40% of RA patients remain active. This suggests the need for discovery of other disease specific pathways which may be targeted.
The authors were able to identify an enriched population of CD55+ lining FLS in pannus of relapsed RA synovium in comparison with synovium in remission. Both interferon-α and FGF 10-FGFR1 signaling pathways were activated in CD 55+ lining FLS cells, however both these were independent of each other. They were able to demonstrate attenuation of bone erosion in both in-vitro and rat models after blockade of FGFR1 signaling using siRNA and FGFR1 inhibitor molecule. They were also able to demonstrate the involvement of FGF 10-FGFR1 signaling in osteoclastogenesis in relapsed RA. Targeting FGF 10-FGFR1 pathway may provide new opportunities to treat relapsed RA. Given the previously well elucidated important role of FLS in RA pathogenesis, this pathway appears to have a high translation value.
The renoprotective role of sodium glucose cotransporter 2 (SGLT2) inhibitors has already been revealed in large cardiovascular outcome trials in type 2 diabetes. The authors have explored renal protective potential of SGLT2 inhibitor empaglifozin on lupus prone MRL/lpr mice with nephritis. A CRISPR/Cas9 system was used to generate a SGLT2 knock out podocyte line.
They were able to show reduction in Ig G anti dsDNA levels, serum creatinine and proteinuria in them. Pathologically a reduction in both glomerular and tubulointerstitial damages was demonstrated post the drug administration.
Autophagy is known to play a protective role in LN podocyte injury.
Expression of SGLT 2 was upregulated on podocytes of MRL/lpr mice with nephritis and lupus nephritis (LN) patients, this was associated with podocyte injury by inhibiting autophagy. SGLT-2 inhibitors enhanced the autophagy process by reducing the expression of mTORC 1 signalling.
There is still a huge gap in the therapeutic armamentarium of LN, given that the proportion of patients developing end stage renal disease by 10 years after diagnosis has remained static in the last few decades. Several new molecules targeting the inflammatory pathways are being investigated to bridge this gap. In this context, non immunosuppressive renoprotective medications are attractive if they are also proven to be efficacious in clinical studies of LN.
