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

Rullo OJ, Woo JM, Parsa MF, Hoftman AD, Maranian P, Elashoff DA, Niewold TB, Grossman JM, Hahn BH, McMahon M, McCurdy DK, Tsao BP - Arthritis Res. Ther. (2013)

Bottom Line: 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).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%).

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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.

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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.
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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.

Mentions: When baseline SLEDAI was evaluated independently of AMS, there was no correlation at the time of blood draw with cOPN (r = 0.09, P = 0.6) or with cNGAL (r = -0.18, P = 0.3) in the pSLE sample. Conversely, there was an association of increased cNGAL with worsening SLEDAI in pSLE (Figure 2A); the threshold between persistently inactive or active disease was characterized by a SLEDAI of 4 over the 6-month period, and improved or worsening was defined as a threshold SLEDAI change of greater than or equal to 4 compared to baseline. Although there was no association of cOPN with future flare (P ≥ 0.6) in either the pSLE or aSLE longitudinal cohorts, when pSLE and aSLE patients were grouped by highest or lowest quartile cOPN at baseline (See Table 2 for clinical features), mean AMS at 6 months was increased in subjects with high baseline cOPN (pSLE: 5.3 vs. 2.1, P = 0.01; aSLE: 4.6 vs. 2.7, P = 0.01) (Figure 2B), but not in subjects with baseline cNGAL in the top quartile (Figure 2B).


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

Rullo OJ, Woo JM, Parsa MF, Hoftman AD, Maranian P, Elashoff DA, Niewold TB, Grossman JM, Hahn BH, McMahon M, McCurdy DK, Tsao BP - Arthritis Res. Ther. (2013)

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.
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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.
Mentions: When baseline SLEDAI was evaluated independently of AMS, there was no correlation at the time of blood draw with cOPN (r = 0.09, P = 0.6) or with cNGAL (r = -0.18, P = 0.3) in the pSLE sample. Conversely, there was an association of increased cNGAL with worsening SLEDAI in pSLE (Figure 2A); the threshold between persistently inactive or active disease was characterized by a SLEDAI of 4 over the 6-month period, and improved or worsening was defined as a threshold SLEDAI change of greater than or equal to 4 compared to baseline. Although there was no association of cOPN with future flare (P ≥ 0.6) in either the pSLE or aSLE longitudinal cohorts, when pSLE and aSLE patients were grouped by highest or lowest quartile cOPN at baseline (See Table 2 for clinical features), mean AMS at 6 months was increased in subjects with high baseline cOPN (pSLE: 5.3 vs. 2.1, P = 0.01; aSLE: 4.6 vs. 2.7, P = 0.01) (Figure 2B), but not in subjects with baseline cNGAL in the top quartile (Figure 2B).

Bottom Line: 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).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%).

View Article: PubMed Central - HTML - PubMed

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.

Show MeSH
Related in: MedlinePlus