Biomarker Commons

Biomarkers for systemic lupus erythematosus.

Transl Res. 2012 Apr;159(4):326-42

Authors: Ahearn JM, Liu CC, Kao AH, Manzi S

Abstract
The urgent need for lupus biomarkers was demonstrated in September 2011 during a Workshop sponsored by the Food and Drug Administration: Potential Biomarkers Predictive of Disease Flare. After 2 days of discussion and more than 2 dozen presentations from thought leaders in both industry and academia, it became apparent that highly sought biomarkers to predict lupus flare have not yet been identified. Even short of the elusive biomarker of flare, few biomarkers for systemic lupus erythematosus (SLE) diagnosis, monitoring, and stratification have been validated and employed for making clinical decisions. This lack of reliable, specific biomarkers for SLE hampers proper clinical management of patients with SLE and impedes development of new lupus therapeutics. As such, the intensity of investigation to identify lupus biomarkers is climbing a steep trajectory, lending cautious optimism that a validated panel of biomarkers for lupus diagnosis, monitoring, stratification, and prediction of flare may soon be in hand.

PMID: 22424435 [PubMed - indexed for MEDLINE]

Recipe for a new imaging biomarker: carefully combine target, reagent, and technology.

Kidney Int. 2012 Jan;81(2):129-31

Authors: Kobayashi H, Choyke PL

Abstract
A careful combination of biological targeting moieties (C3 fragments), imaging reagents (a small particle of iron oxide), and appropriate technology (T2-weighted magnetic resonance imaging) is the key to the successful development of an imaging agent for glomerulonephritis. This recipe applies to virtually any molecular imaging probe for the kidney and throughout the body. However, each organ and disease requires a unique combination of these three components in order to achieve success.

PMID: 22205431 [PubMed - indexed for MEDLINE]

Detection of glomerular complement C3 fragments by magnetic resonance imaging in murine lupus nephritis.

Kidney Int. 2012 Jan;81(2):152-9

Authors: Sargsyan SA, Serkova NJ, Renner B, Hasebroock KM, Larsen B, Stoldt C, McFann K, Pickering MC, Thurman JM

Abstract
One of the challenges of treating patients with glomerulonephritis is to accurately assess disease activity. As renal biopsies are routinely stained for deposits of C3 activation fragments and glomerular C3 deposits are found in most forms of glomerulonephritis, we sought to determine whether a relatively noninvasive measure of C3 fragment deposition in the kidney can serve as a good biomarker of disease onset and severity. We recently developed a magnetic resonance imaging (MRI)-based method of detecting glomerular C3 and used this to track the progression of renal disease in the MRL/lpr mouse model of lupus nephritis using superparamagnetic iron oxide nanoparticles conjugated to complement receptor type 2 as a targeting agent. Quantitative immunofluorescence showed that glomerular C3b/iC3b/C3d deposition progressively increased with disease activity, a finding replicated by the T2-weighted MRI. The T2 relaxation times decreased with disease activity in the cortex and medulla of the MRL/lpr but not in MRL/Mpj control mice. Thus, MRI contrast agents targeted to glomerular C3 fragments can be used to noninvasively monitor disease activity in glomerulonephritis. As therapeutic complement inhibitors are used in patients with renal disease, this method, should it become feasible in humans, may identify those likely to benefit from complement inhibition.

PMID: 21956190 [PubMed - indexed for MEDLINE]

Prospective assessment of C4d deposits on circulating cells and renal tissues in lupus nephritis: a pilot study.

Lupus. 2012 Jan;21(1):13-26

Authors: Batal I, Liang K, Bastacky S, Kiss LP, McHale T, Wilson NL, Paul B, Lertratanakul A, Ahearn JM, Manzi SM, Kao AH

Abstract
Complement activation plays a key role in the pathogenesis of lupus nephritis (LN), a severe complication of systemic lupus erythematosus (SLE). We prospectively evaluated 15 LN subjects and two control groups: 13 non-SLE renal subjects (control A) and 239 SLE subjects without LN (control B). All had C4d levels on circulating erythrocytes (E-C4d), reticulocytes (R-C4d) and platelets (P-C4d) measured by flow cytometry, while C4d deposition in renal tissue was semiquantitatively assessed in LN subjects and control A using immunoperoxidase staining. Compared with control A, LN biopsies had higher glomerular-C4d scores (p = 0.003), which were associated with more frequent granular glomerular immunofluorescence staining and electron dense deposits (p < 0.001). Compared with control A and B groups, LN subjects had higher E-C4d (p = 0.002 and p = 0.005) and R-C4d levels (p = 0.002 and p = 0.008), respectively. LN subjects were more likely to have P-C4d compared with control A (p = 0.016). In LN, only E-C4d correlated with National Institutes of Health (NIH) activity index (r = 0.55, p = 0.04). In conclusion, LN biopsies showed frequent glomerular-C4d staining associated with immune complex deposits. LN subjects had higher E-C4d and R-C4d levels compared with both control groups. E-C4d levels also correlated with NIH activity index. These findings suggest a potential role of C4d on circulating cells as a biomarker for lupus nephritis.

PMID: 21959138 [PubMed - indexed for MEDLINE]

Antinucleosome antibodies as a potential biomarker for the evaluation of renal pathological activity in patients with proliferative lupus nephritis.

Lupus. 2011 Nov;20(13):1404-10

Authors: Hung WT, Chen YM, Lan JL, Chen HH, Chen YH, Chen DY, Hsieh CW, Wen MC

Abstract
The objective of this study is to evaluate the correlation between antinucleosome antibodies and renal pathological activity in patients with proliferative lupus nephritis (LN). We evaluated 36 patients with proliferative LN, 14 non-renal lupus patients and 10 healthy volunteers. Lupus activity was assessed using the British Isles Lupus Assessment Group 2004 (BILAG 2004) index, serum anti-double stranded DNA (anti-dsDNA) levels, serum complement levels and daily urinary protein levels. All 36 lupus nephritis patients received renal biopsy. Antinucleosome antibodies were detected by enzyme-linked immunosorbent assay (ELISA). Our results showed that levels of serum antinucleosome antibodies were significantly higher in LN patients (median 90.35 units/ml, interquartile range [IQR] 37.38-135.23) than in non-renal SLE patients (median 5.45 units/ml, IQR 2.6-28.93, p <0.05) and in healthy volunteers (median 3.35 units/ml, IQR 2.95-5.23, p <0.001). Serum levels of antinucleosome antibodies were positively correlated with BILAG index (Spearman's r = 0.645, p <0.001) and serum anti-dsDNA antibody levels (r(s) = 0.644, p <0.01), while serum levels of antinucleosome antibodies were negatively correlated with serum levels of C3 (r(s) = -0.400, p <0.01) and C4 (r(s) = -0.300, p <0.05). Serum levels of antinucleosome antibodies were positively correlated with the histological activity index of LN (r(s) = 0.368, p <0.05). However, there was no significant correlation between serum levels of antinucleosome antibodies and the histological chronicity index. In conclusion, the serum level of antinucleosome antibodies is a potential biomarker for early recognition of renal involvement and evaluation of disease activity in SLE. Our preliminary results suggested that serum levels of antinucleosome antibodies might be a potential biomarker in evaluating pathological activity of LN.

PMID: 21946514 [PubMed - indexed for MEDLINE]

Deranged bioenergetics and defective redox capacity in T lymphocytes and neutrophils are related to cellular dysfunction and increased oxidative stress in patients with active systemic lupus erythematosus.

Clin Dev Immunol. 2012;2012:548516

Authors: Li KJ, Wu CH, Hsieh SC, Lu MC, Tsai CY, Yu CL

Abstract
Urinary excretion of N-benzoyl-glycyl-Nε-(hexanonyl)lysine, a biomarker of oxidative stress, was higher in 26 patients with active systemic lupus erythematosus (SLE) than in 11 non-SLE patients with connective tissue diseases and in 14 healthy volunteers. We hypothesized that increased oxidative stress in active SLE might be attributable to deranged bioenergetics, defective reduction-oxidation (redox) capacity, or other factors. We demonstrated that, compared to normal cells, T lymphocytes (T) and polymorphonuclear neutrophils (PMN) of active SLE showed defective expression of facilitative glucose transporters GLUT-3 and GLUT-6, which led to increased intracellular basal lactate and decreased ATP production. In addition, the redox capacity, including intracellular GSH levels and the enzyme activity of glutathione peroxidase (GSH-Px) and γ-glutamyl-transpeptidase (GGT), was decreased in SLE-T. Compared to normal cells, SLE-PMN showed decreased intracellular GSH levels, and GGT enzyme activity was found in SLE-PMN and enhanced expression of CD53, a coprecipitating molecule for GGT. We conclude that deranged cellular bioenergetics and defective redox capacity in T and PMN are responsible for cellular immune dysfunction and are related to increased oxidative stress in active SLE patients.

PMID: 22007252 [PubMed - indexed for MEDLINE]

Anti-C1q antibodies have higher correlation with flares of lupus nephritis than other serum markers.

Lupus. 2011 Oct;20(12):1267-74

Authors: Akhter E, Burlingame RW, Seaman AL, Magder L, Petri M

Abstract
OBJECTIVE: Autoantibodies are important in the diagnosis and classification of systemic lupus erythematosus (SLE), but whether they correlate with changes in disease activity within individual patients is controversial. We assessed the association between changes in SLE global and renal activity and changes in several autoantibodies and cell adhesion molecules in patients with SLE.
METHODS: Stored sera collected at two or three clinic visits from each of 49 SLE patients (91% female, 59% African-American, 31% Caucasian, 10% other ethnicity, 38% under 30 years, 41% between 30-44 years, and 21% 45-63 years) were analyzed. The visits were chosen to include one visit with proteinuria, and one or two without, for each patient. Global disease activity was measured by the Physician's Global Assessment (PGA), SELENA-SLEDAI (SLE Disease Activity Index modified to exclude anti-dsDNA and complement) and renal activity assessed by urine protein (by urine dipstick) and Renal Activity Score. Sera were assayed for anti-C1q, anti-chromatin, anti-dsDNA, anti-ribosomal P, monocyte chemotactic protein-1 (MCP-1), vascular cell adhesion molecule (VCAM) intercellular adhesion molecule (ICAM) and complement. The associations between changes in disease activity and changes in biomarker levels were assessed.
RESULTS: In terms of global disease activity, anti-C1q had the highest association with the PGA (p = 0.09) and was strongly associated with modified SELENA-SLEDAI (p = 0.009). In terms of renal activity, anti-C1q had the highest association with proteinuria (p = 0.079), and was strongly associated with Renal Activity Score (p = 0.006).
CONCLUSION: Anti-C1q performed the best of the potential biomarkers, being significantly associated with the modified SELENA-SLEDAI and with the Renal Activity Score. This study indicates the potential superior utility of anti-C1q over anti-dsDNA and other measures to track renal activity.

PMID: 21813587 [PubMed - indexed for MEDLINE]

Usefulness of pleural effusion antinuclear antibodies in the diagnosis of lupus pleuritis.

Lupus. 2011 Oct;20(10):1042-6

Authors: Toworakul C, Kasitanon N, Sukitawut W, Wichinun R, Louthrenoo W

Abstract
We performed this study to determine sensitivity and specificity of pleural effusion antinuclear antibodies (ANA) at a titer of ≥1 : 160, and the ratio of pleural effusion to serum ANA of ≥1, to distinguish between pleural fluid from lupus pleuritis and other causes. A prospective study of 54 patients with pleural effusion (12 lupus pleuritis, seven parapneumonic effusion, 26 malignancy-associated pleural effusions, nine transudative effusions) was performed. ANA at a titer of ≥1 : 160 were found in 11 of 12 lupus pleuritis samples, and in four of 42 pleural effusions from non-systemic lupus erythematosus (SLE) patients. The pleural effusion ANA at a titer of ≥1 : 160 gave a sensitivity of 91.67% for lupus pleuritis, with a specificity of 83.33% when compared with all other pleural effusions, 90.91% when compared with exudative effusion (parapneumonic effusion and malignancy-associated effusion) and 55.56% when compared with the transudative pleural effusion group. Using the ratio of pleural effusion to serum ANA of ≥1, the sensitivity and the specificity decreased to 75.00% and 78.57%, respectively. This study provides further evidence that the pleural effusion ANA at a titer of ≥1 : 160 is a sensitive and specific diagnostic biomarker for lupus pleuritis in patients with lupus. However, pleural effusion ANA can occasionally be found in other conditions.

PMID: 21659420 [PubMed - indexed for MEDLINE]