Background and aims Skin rash can often herald the onset of a systemic disease flare in systemic lupus. The subtype of skin lesion may confer a differential risk of renal involvement. We hypothesised that renal flares may exhibit crosstalk between skin and kidneys and that similar molecular mechanisms may underlie skin and renal disease.

Methods We used systems biology approaches to integrate the regulatory events occurring in subacute cutaneous lupus erythematosus (sCLE, n=43) and discoid lupus erythematosus (DLE, n=47) and compared with those in the ERCB lupus nephritis (LN) class II+IV cohort (n=22).

Results Shared transcriptional networks in SLE skin lesions versus LN kidney biopsies reflect similar pathway regulation (p-value<0.05) including complement, B-cells, dendritic cells (DCs), IL4, IL8, and inflammasome signalling pathways.

IL-12 signalling and production in macrophages, IL-3, IL-15 signalling pathways were regulated only in LN glomeruli and sCLE rashes, while there were metabolic pathways unique to DLE.

CCL21 mRNA expression was specifically up-regulated in sCLE and LN tubulointerstitium and correlated with eGFR, which suggests it may play a role in cutaneous and renal lupus pathogenesis.

Conclusions SCLE, which is associated with a higher risk of systemic disease involvement compared with DLE, shares overlapping gene regulation with lupus nephritis. Dendritic cell pathways and associated upregulation of the CCR7 ligand CCL21, that is involved in recruitment of immune effector cells, may serve as a marker for sCLE patients at risk for LN. These data thus identify potentially important molecular targets for novel therapies in cutaneous and renal lupus.