Plasma levels of osteopontin identify patients at risk for organ damage in systemic lupus erythematosus

Abstract

Introduction: Osteopontin (OPN) has been implicated as a mediator of Th17 regulation via type I interferon (IFN) receptor signaling and in macrophage activity at sites of tissue repair. This study assessed whether increased circulating plasma OPN (cOPN) precedes development of organ damage in pediatric systemic lupus erythematosus (pSLE) and compared it to circulating plasma neutrophil gelatinase-associated lipocalin (cNGAL), a predictor of increased SLE disease activity.

Methods: cOPN and cNGAL were measured in prospectively followed pSLE (n=42) and adult SLE (aSLE; n=23) patients and age-matched controls. Time-adjusted cumulative disease activity and disease damage were respectively assessed using adjusted-mean SLE disease activity index (SLEDAI) (AMS) and SLICC/ACR damage index (SDI).

Results: Compared to controls, elevated cOPN and cNGAL were observed in pSLE and aSLE. cNGAL preceded worsening SLEDAI by 3-6 months (P=0.04), but was not associated with increased 6-month AMS. High baseline cOPN, which was associated with high IFNalpha activity and expression of autoantibodies to nucleic acids, positively correlated with 6-month AMS (r=0.51 and 0.52, P=0.001 and 0.01 in pSLE and aSLE, respectively) and was associated with SDI increase at 12 months in pSLE (P=0.001). Risk factors for change in SDI in pSLE were cOPN (OR 7.5, 95% CI [2.9-20], P=0.03), but not cNGAL, cumulative prednisone, disease duration, immunosuppression use, gender or ancestry using univariate and multivariate logistic regression. The area under the curve (AUC) when generating the receiver-operating characteristic (ROC) of baseline cOPN sensitivity and specificity for the indication of SLE patients with an increase of SDI over a 12 month period is 0.543 (95% CI 0.347-0.738; positive predictive value 95% and negative predictive value 38%).

Conclusion: High circulating OPN levels preceded increased cumulative disease activity and organ damage in SLE patients, especially in pSLE, and its value as a predictor of poor outcome should be further validated in large longitudinal cohorts.

Figure 1

Indicators of disease and cumulative disease activity in pediatric- and adult-onset systemic lupus erythematosus (pSLE and aSLE). (A) Circulating plasma osteopontin (cOPN) and neutrophil gelatinase-associated lipocalin (cNGAL) levels in pSLE and aSLE are increased compared with unrelated age-matched healthy young controls (H.C.) and unrelated healthy adults (H.A.), respectively. pSLE patients with active disease are represented by open squares. (B) Increased 6-month adjusted-mean SLE disease activity index (AMS) is seen in pSLE and aSLE patients who have an increase in Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index scores (SDI) at the end of the 12-month follow up period.

Figure 2

Association of circulating plasma osteopontin (cOPN), but not circulating neutrophil gelatinase-associated lipocalin (cNGAL) with adjusted-mean systemic lupus erythematosus disease activity index (AMS) at the 6-month interval. (A) Baseline cNGAL in pediatric-onset systemic lupus erythematosus (pSLE) was lower in patients with persistently inactive disease over a 6-month period, but did not differentiate among patients with active disease at baseline, which improves (Active:I); remains persistently active (Active:P); or worsens over 6 months. (B) Increased 6-month AMS in pSLE is associated with baseline high cOPN (OPNhi; osteopontin levels in the top quartile) compared with cOPN in the bottom quartile (OPNlo), but not with baseline high cNGAL levels (NGALhi and NGALlo, also defined as top and bottom quartile, respectively). (C) cOPN at baseline correlates with 6-month AMS in pSLE (n = 42) and in adult-onset SLE (aSLE) (n = 23). (D) There is no correlation of baseline cNGAL levels in the total pSLE cohort or in aSLE. SLEDAI, SLE disease activity index.

Figure 3

Baseline circulating osteopontin levels correlated with disease-related damage accumulated over the subsequent twelve months. Mean baseline natural log-transformed circulating osteopontin (lncOPN) was higher in pediatric- and adult-onset systemic lupus erythematosus (pSLE and aSLE) patients who had an increase in (SDI) scores over the 12-month study period (left), but not mean natural log-transformed circulating neutrophil gelatinase-associated lipocalin (lncNGAL) (right). SDI, Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index.