Potential Biomarker Of Disease Activity Research Articles

Plasma osteopontin levels are associated with disease activity in the patients with multiple sclerosis and neuromyelitis optica

Osteopontin (OPN) up-regulates pro-inflammatory cytokines from both T helper type 1 and T helper type 17 cell pathways. We measured plasma OPN levels in Japanese multiple sclerosis (MS) and neuromyelitis optica (NMO) patients to investigate its value as a potential biomarker of disease activity. In NMO patients, plasma OPN levels were significantly higher than those in healthy individuals, being equivalent to those in MS patients. In both NMO and MS patients, OPN levels were significantly higher during relapse compared with remission. There was also a significant positive correlation between Expanded Disability Status Scale of Kurzke scores and plasma OPN levels in both NMO and MS patients, and plasma OPN levels were significantly higher in patients with secondary progressive MS compared with those with relapsing-remitting MS. Diagnostic sensitivity and specificity of plasma OPN for MS and NMO during the relapse phase were 100% and 50%, respectively (cut-off point: 31.3ng/ml). Thus, elevated plasma OPN levels could be a potential biomarker for not only MS but also NMO. These are the first results to suggest that plasma OPN in NMO patients may be a useful marker, playing an important role in inflammation, disease activity, and disease progression, as well as MS.

BAFF/APRIL system in pediatric OMS: relation to severity, neuroinflammation, and immunotherapy

BackgroundB-cell dysregulation has been implicated but not fully characterized in pediatric opsoclonus-myoclonus syndrome (OMS), a neuroblastoma-associated neuroinflammatory disorder.ObjectiveTo assess the role of B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), two critical B cell-modulating cytokines, as potential biomarkers of disease activity and treatment biomarkers in OMS.MethodsSoluble BAFF and APRIL were measured in cerebrospinal fluid (CSF) and serum by ELISA in 433 children (296 OMS, 109 controls, 28 other inflammatory neurological disorders (OIND)). BAFF-R receptors on circulating CD19+ B cells were measured by flow cytometry. A blinded scorer rated motor severity on the OMS Evaluation Scale. Immunotherapies were evaluated cross-sectionally and longitudinally.ResultsThe mean CSF BAFF concentration, which was elevated in untreated OMS and OIND, correlated with OMS severity category (P = 0.006), and reduction by adrenocorticotropic hormone or corticotropin (ACTH) (−61%) or corticosteroids (−38%) was seen at each level of severity. In contrast, CSF APRIL was normal in OMS and OIND and unaffected by immunotherapy. When the entire OMS dataset was dichotomized into ‘high’ versus ‘normal’ CSF BAFF concentration, the phenotype of the high group included greater motor severity and number of CSF oligoclonal bands, and a higher concentration of inflammatory chemokines CXCL13 and CXCL10 in CSF and CXCL9 and CCL21 in serum. Serum APRIL was 6.7-fold higher in the intravenous immunoglobulins (IVIg) group, whereas serum BAFF was 2.6-fold higher in the rituximab group. The frequency of B cell BAFF-R expression was similar in untreated and treated OMS. Longitudinal studies of CSF BAFF revealed a significant decline in ACTH-treated patients (with or without rituximab) (P < 0.0001). Longitudinal studies of serum APRIL showed a 2.9-fold increase after 1 to 2 g/kg IVIg monotherapy (P = 0.0003).ConclusionsStriking distinctions in BAFF/APRIL signaling were found. OMS displayed heterogeneity in CSF BAFF expression, which met many but not all criteria as a potential biomarker of disease activity. We speculate that CSF BAFF may have more utility in a biomarker panel than as a stand-alone biomarker, and that the selective upregulation of both serum APRIL by IVIg and BAFF by rituximab, as well as downregulation of CSF BAFF by ACTH/steroids, may have utility as treatment biomarkers.

Myeloid related protein induces muscle derived inflammatory mediators in juvenile dermatomyositis

IntroductionThe aetiopathogenesis of juvenile dermatomyositis (JDM) remains poorly understood. In particular the contribution of monocytes or macrophages, which are frequently observed to be an infiltrate within muscle tissue very early in the disease process, is unknown. We hypothesised that these cells secrete the pro-inflammatory myeloid related protein (MRP) 8/14 which may then contribute to muscle pathology in JDM.MethodsIn this study of 56 JDM patients, serum MRP8/14 levels were compared with clinical measures of disease activity. Muscle biopsies taken early in disease were assessed by immunohistochemistry to determine the frequency and identity of MRP-expressing cells. The effects of MRP stimulation and endoplasmic reticulum (ER) stress on muscle were tested in vitro. Serum or supernatant levels of cytokines were analyzed by multiplex immunoassay.ResultsSerum MRP8/14 correlated with physician’s global assessment of disease activity in JDM (R = 0.65, p = 0.0003) and muscle strength/endurance, childhood myositis assessment score (CMAS, R = −0.55, p = 0.004). MRP8/14 was widely expressed by CD68+ macrophages in JDM muscle tissue. When cultured with human myoblasts, MRP8 led to the secretion of MCP-1 and IL-6, which was enhanced by ER stress. Both inflammatory mediators were detected in significantly higher levels in the serum of JDM patients compared to healthy controls.ConclusionsThis study is the first to identify serum MRP8/14 as a potential biomarker for disease activity in JDM. We propose that tissue infiltrating macrophages secreting MRP8/14 may contribute to myositis, by driving the local production of cytokines directly from muscle.

MCP-1 in urine as biomarker of disease activity in Systemic Lupus Erythematosus

Conventional clinical parameters are not sensitive or specific enough for detecting ongoing disease activity in the Systemic Lupus Erythematosus (SLE). Measurement of cytokines in urine is an encouraging approach to detection of early flares in this disease. Here we have profiled 27 different cytokines, chemokines and celular growth factors in the urine of 48 patients previously diagnosed of SLE as potential biomarkers of disease activity. Correlation analysis with Bonferroni correction showed that MCP-1 was the only immune mediator which levels in urine correlated directly with the SLE Disease Activity Index 2000 (SLEDAI-2K) score (correlation coefficient, p): MCP-1 (0.45,0.003). MCP-1 correlated inversely with levels of C3 complement protein in serum (−0.50,0.001). MCP-1 showed significant higher levels in patients with severe disease activity in comparison with those exhibiting mild activity. Levels of this chemokine were also higher in patients with severe disease activity in comparison with patients with inactive disease and healthy controls. Areas under receiver operating characteristic curves (AUROC) for detection of severe disease (SLEDAI⩾8) was as follows for MCP-1: [AUROC, (IC95%), p]: [0.81 (0.65–0.96) 0.003]. In addition, MCP-1 showed a good result in the AUROC analysis for detecting renal involvement [0.70 (0.52–0.87) 0.050]. When correlation analysis were repeated excluding those patients with active renal disease (n=14), levels of MCP-1 in urine kept on showing a significant positive association with SLEDAI-2K score. In conclusion, multiplex-based cytokine profiling in urine demonstrated the superiority of MCP-1 over a wide range of cytokines as biomarker of disease activity in SLE.

Potential biomarkers for disease activity in Takayasu's arteritis

Sun et al. recently reported matrix metalloproteinase-9 (MMP-9) and interleukin-6 (IL-6) as potential biomarkers for disease activity in Takayasu's arteritis (TA) in Chinese population [1]. Authors determined serum levels ofMMPs (MMP-3 and 9), tissue inhibitor ofMMPs (TIMP-1) and IL-6 in subjectswith TA and correlatedwith the disease activity of the disease. In a subgroup offifteenTA subjects they demonstrated that levels ofMMP-9 and IL-6 are able to predict the imagingoutcomeof thepatients with TA, but at the same time failed to notice any significant correlation between the pathological findings and the serum levels of MMP-9 and MMP-3 and IL-6. While reading this article, we found that the authors missed a few important studies to discuss in context to this particular field, where importance of IL-6 andMMPs-TIMP-1 has been established as potential biomarkers for this disease. Noris et al [2] in Italian population demonstrated a close relation of serum IL-6 with disease activity and suggested that it could contribute to vasculitic lesion in TA and could be relevant in the setting of therapeutic management of TA. In another study from Japan, Matsuyama et al [3] suggested that monitoring of circulating levels of MMP-2 as a helpful marker in diagnosing TA and those of MMP-3 and MMP-9 as disease activity markers might help provide adequate evaluation of treatment and guide therapeutic decision making for individual patients with TA. Our research group in India has also demonstrated importance of different MMPs (MMP-1, MMP-2, MMP-3, MMP-9 and TIMP-1) and their significant correlation with oxidative stress biomarkers (8-isoPGF2α and nitrite levels) in Takayasu's arteritis [4,5]. The etiopathogenesis of Takayasu's arteritis disease remains enigmatic, and various mechanisms such as post-infective, autoimmune, ethnic susceptibility and a genetic predisposition have been postulated [4,6]. As concluding remarks, we want to emphasize the fact that TA has been reported all over theworld with awide variation in its prevalence in different geographical regions. Moreover, it has been reported to cause different aortic lesion at different places in different countries [7]. Comparing and thoroughly analyzing the results from various studies reported worldwide will be of great help to provide a correct direction for future research on TA, as each and every researcher in this particular area is teaming to address the questionwhether any of thesemolecules can beused as amarker tomonitor the clinical course of the disease or to predict the disease exacerbations. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [8].

MMP-9 and IL-6 are potential biomarkers for disease activity in Takayasu's arteritis

Takayasu arteritis (TA) is an idiopathic vasculitis which primarily affects large elastic arteries and the disease onset and progress are often insidious, and the systemic manifestations are always absent or go unrecognized [1,2]. Furthermore, TA disease tends to progress despite treatment with glucocorticoid and/or immunosuppressive agents. So, it is crucial to find appropriate biomarkers to monitor TA disease activity and possibly predict exacerbations, in order to aid early treatment; however, traditional biomarkers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) lack the sensitivity and specificity to accurately monitor disease status [3,4].

521 Serum NT-3 and NT-4 Levels are Associated with Clinical Severity in Asthmatic Children

BackgroundNeuronal modulation of inflammation and airway hyperresponsiveness has been well described in asthma and neurotrophins provide the link between inflammation and neuronal dysfunction. In humans, elevated BDNF, NGF and NT-3 levels have been found in bronchoalveolar lavage fluid (BALF) following allergen provocation. Moreover, BDNF levels are significantly higher in untreated asthmatic patients in comparison to those treated with inhaled glucocorticoids and non asthmatic controls. It has also been shown that allergic inflammation increases local all 4 neurotrophins production that are important mediators of eosinophil survival in BALF. The aim of this study was to analyze if levels of neurotrophins in serum of asthmatic pediatric patients are altered in the course of disease (exacerbation and asymptomatic period) and therefore may serve as potential biomarkers for disease activity or symptoms severity.MethodsIn the study we included 98 children diagnosed with asthma. The blood was collected twice: during exacerbation and in the asymptomatic period. The serum levels of 4 neurotrophins (BDNF, NGF, NT-3, NT-4) were analyzed with use of DuoSet ELISA Development Kit (R&D). Statistical analysis was performed with Statistica v. 9.0.ResultsAnalysis revealed no significant differences in neurotrophins levels in serum between asthmatic patients during asthma exacerbation and asymptomatic period. However, we found that serum levels of NT-3 and NT4 correlate with disease severity, being significantly lower in mild asthmatics as compared to patients with moderate and severe asthma (P < 0.01).ConclusionsOur results suggest that neurotrophins levels do not seem to correlate with the clinical symptoms activity in the course of asthma, however 2 of them (NT-3 and NT-4) correlate with disease severity.

Mannose binding lectin: a biomarker of systemic lupus erythematosus disease activity

IntroductionA role for mannose binding lectin (MBL) in autoimmune diseases has been demonstrated earlier and elevated level of MBL has been shown in systemic lupus erythematosus (SLE) patients. In the current study, we investigated MBL as a potential biomarker for disease activity in SLE.MethodsIn a case control study SLE patients (93 females) and 67 age, sex, ethnicity matched healthy controls were enrolled. Plasma MBL levels were quantified by enzyme linked immunosorbent assay (ELISA). Clinical, serological and other markers of disease activity (C3, C4 and anti-dsDNA) were measured by standard laboratory procedures.ResultsPlasma MBL levels were significantly high in SLE patients compared to healthy controls (P < 0.0001). MBL levels were variable in different clinical categories of SLE. Lower levels were associated with musculoskeletal and cutaneous manifestations (P = 0.002), while higher and intermediate MBL levels were significantly associated with nephritis in combination with other systemic manifestations (P = 0.01 and P = 0.04 respectively). Plasma MBL correlated with systemic lupus erythematosus disease activity index (SLEDAI) (P = 0.0003, r = 0.36), anti-dsDNA (P < 0.0001, r = 0.54), proteinuria (P < 0.0001, r = 0.42) and negatively correlated with C3 (P = 0.007, r = -0.27) and C4 (P = 0.01, r = -0.29).ConclusionsPlasma MBL is a promising marker in the assessment of SLE disease activity.

The fibrinogen cleavage product Aα-Val360, a specific marker of neutrophil elastase activity in vivo

BackgroundAlpha-1-antitrypsin (A1AT) deficiency is the only recognised genetic risk factor for chronic obstructive pulmonary disease (COPD), a leading cause of morbidity and mortality worldwide. Since A1AT is the major inhibitor...

Profiling Hypoxia Markers in Pediatric Inflammatory Bowel Disease

Background: Inflammation-associated hypoxia has been studied extensively in murinemodels of inflammatory bowel diseases (IBD), and to a lesser extent in human IBD. Results from studies strongly implicate the potential that circulating or tissue markers of hypoxia could serve as important biomarkers of disease. A systematic analysis of hypoxia markers associated with IBD has not been pursued. Aims: To characterize markers of hypoxia in serum and colon biopsies from patients with IBD colitis and controls without colitis, and to correlate hypoxia markers with severity of disease assessed by histology, pro-inflammatory cytokines, questionnaires, and other laboratory data. Methods: Samples of blood and colon biopsies were obtained from 10 pediatric patients (mean age 13.9±2.7) with active IBD colitis and 8 controls (mean age 14.6±2.1), one of which had quiescent IBD. Protein levels of three hypoxia markers were measured in serum: erythropoietin (EPO), vascular endothelial growth factor (VEGF), and insulin-like growth factor binding protein-1 (IGFBP-1); and four proinflammatory cytokines were measured in tissue: IL-1 beta, IL-6, IL-8, and TNF alpha via an electrochemiluminescence-based ELISA platform. Pediatric Ulcerative Colitis Activity Index (PUCAI) and puberty scores were also collected. A single pathologist, blinded to diagnosis, graded biopsy histology based on a standardized scoring system. Differences by study group or PUCAI category were tested with two-sample t-tests or exact chi-square tests, and differences across histology grade by ANOVA. The monotonic relationship between hypoxia markers and pro-inflammatory cytokines and puberty score was tested with Spearman's correlation coefficient. Results: Patient demographics did not significantly differ by gender (p=0.06), race (p=0.7) or age (p=0.6). Children with active colitis had higher levels of EPO than controls (9.4 vs. 3.4, p=0.03). Notably, serum EPO levels did not correlate with hemoglobin. No significant differences were noted in total circulating VEGF (562 vs. 256, p=0.12) or IGFBP-1 (6716 vs. 3812, p=0.45), however all three serum hypoxia markers differed across histology grade (VEGF p=0.002, EPO p<0.0001, IGFBP-1=0.018). Serum VEGF was significantly correlated with tissue IL-6, IL-8, and TNF alpha (0.62, p=0.006; 0.57, p=0.014; 0.60, p=0.008), as was EPO with IL-6, IL-8, and TNF alpha (0.62, p=0.006; 0.63, p=0.005; 0.72, p=0.0008). VEGF and IGFBP-1 did not significantly differ by puberty score or across PUCAI score. Conclusions: These studies identify at least three hypoxia targets which could be pursued as potential biomarkers for disease activity. We conclude that markers of hypoxia strongly correlate with severity of colitis and that peripheral blood hypoxia markers may be useful surrogates to assess tissue inflammation.

The Course of Life and Health-Related Quality of Life of Adolescents With Inflammatory Bowel Disease

Background: Inflammation-associated hypoxia has been studied extensively in murinemodels of inflammatory bowel diseases (IBD), and to a lesser extent in human IBD. Results from studies strongly implicate the potential that circulating or tissue markers of hypoxia could serve as important biomarkers of disease. A systematic analysis of hypoxia markers associated with IBD has not been pursued. Aims: To characterize markers of hypoxia in serum and colon biopsies from patients with IBD colitis and controls without colitis, and to correlate hypoxia markers with severity of disease assessed by histology, pro-inflammatory cytokines, questionnaires, and other laboratory data. Methods: Samples of blood and colon biopsies were obtained from 10 pediatric patients (mean age 13.9±2.7) with active IBD colitis and 8 controls (mean age 14.6±2.1), one of which had quiescent IBD. Protein levels of three hypoxia markers were measured in serum: erythropoietin (EPO), vascular endothelial growth factor (VEGF), and insulin-like growth factor binding protein-1 (IGFBP-1); and four proinflammatory cytokines were measured in tissue: IL-1 beta, IL-6, IL-8, and TNF alpha via an electrochemiluminescence-based ELISA platform. Pediatric Ulcerative Colitis Activity Index (PUCAI) and puberty scores were also collected. A single pathologist, blinded to diagnosis, graded biopsy histology based on a standardized scoring system. Differences by study group or PUCAI category were tested with two-sample t-tests or exact chi-square tests, and differences across histology grade by ANOVA. The monotonic relationship between hypoxia markers and pro-inflammatory cytokines and puberty score was tested with Spearman's correlation coefficient. Results: Patient demographics did not significantly differ by gender (p=0.06), race (p=0.7) or age (p=0.6). Children with active colitis had higher levels of EPO than controls (9.4 vs. 3.4, p=0.03). Notably, serum EPO levels did not correlate with hemoglobin. No significant differences were noted in total circulating VEGF (562 vs. 256, p=0.12) or IGFBP-1 (6716 vs. 3812, p=0.45), however all three serum hypoxia markers differed across histology grade (VEGF p=0.002, EPO p<0.0001, IGFBP-1=0.018). Serum VEGF was significantly correlated with tissue IL-6, IL-8, and TNF alpha (0.62, p=0.006; 0.57, p=0.014; 0.60, p=0.008), as was EPO with IL-6, IL-8, and TNF alpha (0.62, p=0.006; 0.63, p=0.005; 0.72, p=0.0008). VEGF and IGFBP-1 did not significantly differ by puberty score or across PUCAI score. Conclusions: These studies identify at least three hypoxia targets which could be pursued as potential biomarkers for disease activity. We conclude that markers of hypoxia strongly correlate with severity of colitis and that peripheral blood hypoxia markers may be useful surrogates to assess tissue inflammation.

Expression of K2P5.1 potassium channels on CD4+T lymphocytes correlates with disease activity in rheumatoid arthritis patients

IntroductionCD4+ T cells express K2P5.1 (TWIK-related acid-sensitive potassium channel 2 (TASK2); KCNK5), a member of the two-pore domain potassium channel family, which has been shown to influence T cell effector functions. Recently, it was shown that K2P5.1 is upregulated upon (autoimmune) T cell stimulation. The aim of this study was to correlate expression levels of K2P5.1 on T cells from patients with rheumatoid arthritis (RA) to disease activity in these patients.MethodsExpression levels of K2P5.1 were measured by RT-PCR in the peripheral blood of 58 patients with RA and correlated with disease activity parameters (C-reactive protein levels, erythrocyte sedimentation rates, disease activity score (DAS28) scores). Twenty patients undergoing therapy change were followed-up for six months. Additionally, synovial fluid and synovial biopsies were investigated for T lymphocytes expressing K2P5.1.ResultsK2P5.1 expression levels in CD4+ T cells show a strong correlation to DAS28 scores in RA patients. Similar correlations were found for serological inflammatory parameters (erythrocyte sedimentation rate, C-reactive protein). In addition, K2P5.1 expression levels of synovial fluid-derived T cells are higher compared to peripheral blood T cells. Prospective data in individual patients show a parallel behaviour of K2P5.1 expression to disease activity parameters during a longitudinal follow-up for six months.ConclusionsDisease activity in RA patients correlates strongly with K2P5.1 expression levels in CD4+ T lymphocytes in the peripheral blood in cross-sectional as well as in longitudinal observations. Further studies are needed to investigate the exact pathophysiological mechanisms and to evaluate the possible use of K2P5.1 as a potential biomarker for disease activity and differential diagnosis.

Assessment of serum nitrite as biomarker of disease activity in ankylosing spondylitis

Background The assessment of disease activity in patients with ankylosing spondylitis (AS) continues to be a challenging issue. The currently available markers like C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) show poor correlation with clinical disease activity. There is a need for good biomarkers to assess disease activity. We explored serum nitrite, a stable end product of metabolism of NO, which is known to rise in inflammation, as a potential biomarker of disease activity in AS. Objectives To compare the levels of serum nitrite between patients with AS and healthy controls and to correlate levels of serum nitrite with disease activity in four assessment in ankylosing spondylitis (ASAS) domains. Methods Fifty patients satisfying modified New York criteria for AS were recruited for the study. Patients were assessed in the following ASAS domains: physical function (BASFI), pain (VAS, 0–100), patient global assessment (VAS, 0–100) and inflammation (mean of the two morning stiffness related BASDAI scores). Eighty-seven healthy controls were also included for comparison. Blood samples (12 hours fasting) were obtained and stored for serum nitrite level estimation, which was done by Ding's method. The median levels of serum nitrite were compared between the two groups. Correlation of serum nitrite levels was sought with individual domains of disease activity. Results The median serum nitrite levels in patients with AS were markedly elevated as compared to those in controls (39 μmol/L [IQR 27–50] vs. 4.75 μmol/L [2.53–12], P = 0.001 (Mann-Whitney U test). There was only one patient whose serum nitrite level overlapped with that of controls. Clinical assessment of disease activity (individual ASAS domains-physical function (BASFI), pain, patient global assessment and inflammation (mean of the two morning stiffness) did not show a good correlation with serum nitrite levels. Conclusions Serum nitrite level was increased eight folds in patients with AS when compared with controls. Thus its measurement holds promise in differentiating between inflammatory and mechanical low back pain. However, there was no variation across a range of levels of disease activity making it unsuitable as a biomarker to monitor disease activity in AS.

The role of mannose binding lectin in the pathogenesis of systemic lupus erythematosus

To detect the serum level of mannose binding lectin (MBL) and its genovariation in systemic lupus erythematosus (SLE) patients and to investigate the role of MBL in the pathogenesis of SLE. ELISA was used to measure the serum MBL level of 40 SLE patients and 30 healthy blood donors. Tm genotyping method was used for the first timer in China. Primers and specific fluorophore-labelled hybridization probes for the exon 1 and promoter regions of MBL gene were designed based on the haplotype MBL2(*) LXPA (GenBank X15422). The genotyping of MBL in these two groups were performed using real-time PCR through Light Cycler Instrument. (1) The serum MBL of the SLE patients was 107.2 microg/L, significantly lower than that of the healthy blood donors (290.2 microg/L, P = 0.0002). (2) MBL mutation in exon 1 region was mainly at codon 54, with a mutation rate of 37.1% in the SLE group, significantly higher than that of the control group (13.3%, p = 0.049). (3) Polymorphisms of H/L in MBL gene were present in both SLE patients and controls, and there was no difference in the L allele frequency between the two groups. (4) The serum MBL level of the SLE patients with MBL mutation in codon 54 was 49.8 microg/L, significantly lower than that of the SLE patients without MBL mutation in codon 54 (141.7 microg/L, P = 0.000 27). The SLE disease activity index (SLEDAI) of the SLE patients with MBL mutation in codon 54 was 7.44, significantly lower than that of the SLE patients without MBL mutation in codon 54 (12.87, P = 0.0029). A negative correlation was observed between SLEDAI score and serum MBL (r = -0.48). Mutation occurring in MBL exon 1 region at codon 54 may be a predisposing factor of the pathogenesis of SLE. Serum MBL may be a potential biomarker of disease activity in SLE patients.

Thrombotic Thrombocytopenic Purpura: A Moving Target

Almost 80 years after Eli Moschcowitz published the first description of the disease, most patients with idiopathic thrombotic thrombocytopenic purpura (TTP) were found to have acquired autoantibody inhibitors of the ADAMTS13 metalloprotease. Plasma ADAMTS13 normally cleaves von Willebrand factor within nascent platelet-rich thrombi, and ADAMTS13 deficiency allows unchecked thrombus growth to cause microangiopathic hemolysis, thrombocytopenia, and tissue infarction. At present, ADAMTS13 deficiency with a high-titer inhibitor level appears to be associated with an increased risk of early death and subsequent relapse. Thus, acquired ADAMTS13 deficiency identifies a specific mechanism of TTP and is a potential biomarker of disease activity or risk. At present, two major clinical questions in the field may be summarized as follows. First, by emphasizing TTP caused by ADAMTS13 deficiency, are we in danger of neglecting other causes that should be treated with plasma exchange? Second, should we treat asymptomatic patients who have severe ADAMTS13 deficiency to prevent future disease, and if so, how?

Extracellular matrix metabolites as potential biomarkers of disease activity in wound fluid: lessons learned from other inflammatory diseases?

The new era of pharmacogenetics has identified a potential for individuals to receive customized treatments for a variety of disease states. For such individualized treatments to fulfil their potential, it will be essential for clinicians to be able to monitor disease activity, ideally in a rapid, noninvasive fashion. The accessibility of the skin offers much potential to develop noninvasive tests of metabolic and disease activity for clinical use. Impaired human wound healing in the skin is a chronic inflammatory disorder in which the development of such tests has considerable potential, aiding clinical decision making and monitoring responses to treatment. This review article discusses how studies in other human diseases have highlighted potential biochemical markers (biomarkers) of disease activity in secreted biofluids, as aids to determining disease and metabolic activity within tissues. Using, as examples, lessons learned in the study of disease activity and prognosis of other chronic inflammatory conditions, such as osteoarthritis and periodontal disease, this review highlights the potential of dermal extracellular matrix (ECM) components (collagens, proteoglycans, hyaluronan and glycoproteins) for such uses. The limitations of currently utilized techniques and the concept that analysis of ECM components in wound fluid may represent useful biomarkers of disease activity are also discussed.