Background A noninvasive means to predict the onset and recurrence of lupus is needed to optimise and individualise treatment. Macrophages (Mø) are prominent in inflamed tissues targeted for destruction in SLE. We hypothesised that the principal molecules required for Mø survival and proliferation are biomarkers for SLE. CSF-1 and IL-34 are promising candidates as both (i) bind to cFMS expressed by Mø, thereby promoting Mø survival and proliferation and (ii) promote destructive inflammation. However, IL-34 and CSF-1 have differing functions, which may be related to IL-34, not CSF-1, binding to a second receptor and distinct spatial temporal expressions.

Materials and methods We analysed serum and urine CSF-1 and IL-34 levels in SLE patients with nephritis (LN), arthritis (LA), cutaneous and serositis compared with healthy controls in two large cohorts (ELISA). While serum and urine CSF-1 expression is elevated in each manifestation, CSF-1 is notably higher in LN. In contrast, serum IL-34 expression is dramatically higher in LA, not LN. Thus, we probed for CSF-1 and IL-34 expression in LN (kidney) and LA (synovium). Moreover, we longitudinally tracked serum CSF-1 and IL-34 prior to LN (biopsy proven), with disease activity including flares and during LA in comparison to disease activity

Results

• LN. CSF-1 and IL-34 are expressed in the same and different renal tubular epithelial cells in LN. Elevated serum or urine CSF-1, not IL-34, levels correlate with increasing intra-renal CSF-1 expression and histopathology index. Longitudinally tracking serum CSF-1, not IL-34, levels heralds the initial onset of nephritis and a rise in serum or urine CSF-1 predicts LN recurrences before clinical evidence of renal dysfunction and conventional serologic measures.

• LA. IL-34, not CSF-1, expression is higher in synovial fluid and synovium in LA compared to osteoarthritis and healthy controls and correlates with magnitude of intra-synovial leukocytes. Moreover, intra-synovial IL-34 expression is similar in LA and rheumatoid arthritis. Longitudinally monitoring serum IL-34, not CSF-1, levels track with clinical disease activity in LA and RA.

Conclusions Serial monitoring a rise in serum or urine CSF-1, not IL-34, in SLE reflects renal histopathology and clinical disease activity and the onset and reoccurrences of LN more accurately than conventional laboratory measures. While serial monitoring a rise in serum IL-34, not CSF-1, reflects clinical disease activity in LA. Thus, CSF-1 and IL-34 are inexpensive and accurate potential biomarkers for LN and LA, respectively.