Do classic blood biomarkers of JSLE identify active lupus nephritis? Evidence from the UK JSLE Cohort Study

Abstract

Background Lupus nephritis (LN) affects up to 80% of juvenile-onset systemic lupus erythematosus (JSLE) patients. The value of commonly available biomarkers, such as anti-dsDNA antibodies, complement (C3/C4), ESR and full blood count parameters in the identification of active LN remains uncertain. Methods Participants from the UK JSLE Cohort Study, aged <16 years at diagnosis, were categorized as having active or inactive LN according to the renal domain of the British Isles Lupus Assessment Group score. Classic biomarkers: anti-dsDNA, C3, C4, ESR, CRP, haemoglobin, total white cells, neutrophils, lymphocytes, platelets and immunoglobulins were assessed for their ability to identify active LN using binary logistic regression modeling, with stepAIC function applied to select a final model. Receiver-operating curve analysis was used to assess diagnostic accuracy. Results A total of 370 patients were recruited; 191 (52%) had active LN and 179 (48%) had inactive LN. Binary logistic regression modeling demonstrated a combination of ESR, C3, white cell count, neutrophils, lymphocytes and IgG to be best for the identification of active LN (area under the curve 0.724). Conclusions At best, combining common classic blood biomarkers of lupus activity using multivariate analysis provides a 'fair' ability to identify active LN. Urine biomarkers were not included in these analyses. These results add to the concern that classic blood biomarkers are limited in monitoring discrete JSLE manifestations such as LN.

Biomarkers Associated with Organ-Specific Involvement in Juvenile Systemic Lupus Erythematosus

“…Serum creatinine and eGFR are included in the renal domain of the BILAG score but not in the SLEDAI score. However, multiple studies have demonstrated no significant difference in creatinine or eGFR in patients with active LN [especially in patients with no background renal damage] and both measurements were not useful, as expected in predicting JSLE disease activity in patients with good renal reserve [ 44 , 45 , 46 , 47 , 48 , 49 , 50 ]. Creatinine can vary significantly with muscle mass and whilst the eGFR attempts to adjust for this, both creatinine and eGFR are useful for assessing renal dysfunction due to chronic damage by LN, but they are poor biomarkers of active disease ( Table 1 ).…”

“…Complement activation appears to be central to the pathophysiology of SLE and, due to their cleavage to active C3b and C4b, decreased levels of C3 and C4 are seen in SLE flares and are also included in the classification criteria for SLE [ 10 , 23 , 44 ]. The evidence for supporting the role of serum C3 and C4 measurements as biomarkers of LN in JSLE is mixed; three studies found no significant differences in C3/C4 levels in active LN whilst four studies demonstrated significantly lower levels of C3/C4 in active LN [ 44 , 45 , 46 , 47 , 48 , 50 ]. This variability could be due, in part, to the use of different classifications for definition of a renal flare: e.g.…”

“…Antibodies against double-stranded DNA [dsDNA] are a highly specific feature of JSLE and are also included in the classification criteria [ 23 ]. Interestingly, although historically considered a reliable marker for renal flares in SLE, four studies in JSLE population found no difference in dsDNA levels in active LN compared to other disease manifestations, whilst only one study demonstrated significantly elevated dsDNA levels in children with LN with a poor predictor value for active LN [ 44 , 45 , 46 , 48 , 50 ]. The role of dsDNA as a biomarker for LN flares is likely to be more nuanced, as data from adult SLE studies suggest significant variability of dsDNA titres around the time of renal flare; i.e., an initial increase in dsDNA before the flare, followed by a decrease during the flare [ 52 ].…”

“…There is evidence that levels of C-reactive protein [CRP] usually remain stable during LN flares in JSLE [ 46 ]. Conversely, erythrocyte sedimentation rate [ESR], a non-specific test reflecting both active inflammation and disease pathophysiology [potentially related to polyclonal hypergammaglobulinemia, increase in fibrinogen irrespective of disease activity, as well as by anaemia associated with chronic inflammation or haemolysis], was significantly elevated in flares of LN and was a fair predictor of renal flares in JSLE [ 44 , 45 , 46 ].…”

“…On the other hand, in the SLEDAI score it is defined as urinary protein greater than 0.5 g in 24 h [ 43 ]. It is not surprising that multiple studies have shown increased proteinuria during active LN in JSLE using both the BILAG and SLEDAI criteria [ 44 , 45 , 46 , 49 , 50 ]. Studies that used renal biopsies to diagnose active LN have shown variable results, potentially influenced by the heterogeneity of biopsy scoring systems used in various JSLE studies [ 47 , 50 , 51 ].…”