Biomarker Commons

Impact of a multi-biomarker disease activity test on rheumatoid arthritis treatment decisions and therapy use.

Curr Med Res Opin. 2013 Jan;29(1):85-92

Authors: Li W, Sasso EH, Emerling D, Cavet G, Ford K

Abstract
OBJECTIVE: To assess how use of a multi-biomarker disease activity (MBDA) blood test for rheumatoid arthritis (RA) affects treatment decisions made by health care providers (HCPs) in clinical practice.
RESEARCH DESIGN AND METHODS: At routine office visits, 101 patients with RA were assessed by their HCPs (N = 6), and they provided blood samples for MBDA testing. HCPs completed surveys before and after viewing the MBDA test result, recording dosage and frequency for all planned RA medications and physician global assessment of disease activity. Frequency and types of change in treatment plan that resulted from viewing the MBDA test result were determined.
MAIN OUTCOME MEASURE: Percentage of cases in which the HCP changed the planned treatment after viewing the MBDA test result.
RESULTS: Prior to HCP review of the MBDA test, disease modifying anti-rheumatic drug (DMARD) use by the 101 patients included methotrexate in 62% of patients; hydroxychloroquine 29%; TNF inhibitor 42%; non-TNF inhibitor biologic agent 19%; and other drugs at lower frequencies. Review of MBDA test results changed HCP treatment decisions in 38 cases (38%), of which 18 involved starting, discontinuing or switching a biologic or non-biologic DMARD. Other changes involved drug dosage, frequency or route of administration. The total frequency of use of the major classes of drug therapy changed by <5%. Treatment plans changed 63% of the time when the MBDA test result was perceived as being not consistent or somewhat consistent with the HCP assessment of disease activity. Study limitations: Limited sample size; lack of control group; no longitudinal follow-up.
CONCLUSIONS: The addition of the MBDA test to clinical assessment led to meaningful changes in the treatment plans of 38% of RA patients being cared for by HCPs in office practice. Even though treatment was potentially improved, the overall quantity of drug use was minimally affected.

PMID: 23176063 [PubMed - in process]

Circulating citrullinated vimentin fragments reflect disease burden in ankylosing spondylitis and have prognostic capacity for radiographic progression.

Arthritis Rheum. 2013 Apr;65(4):972-80

Authors: Bay-Jensen AC, Karsdal MA, Vassiliadis E, Wichuk S, Marcher-Mikkelsen K, Lories R, Christiansen C, Maksymowych WP

Abstract
OBJECTIVE: Ankylosing spondylitis (AS) has been considered a seronegative rheumatic disease based on absent or low levels of antibodies against citrullinated proteins. The present study was undertaken to evaluate whether a citrullinated and matrix metalloproteinase-degraded fragment of vimentin (VICM) could be a prognostic biomarker in AS.
METHODS: VICM was measured in serum samples from healthy controls (n=35), control patients with rheumatoid arthritis (RA) (n=47), and patients with AS (n=201). The optimal cutoff for diagnostic sensitivity and specificity was determined by receiver operating characteristic curve analysis. Baseline and 2-year spine radiographs were available from 118 AS patients, and were scored using the modified Stoke AS Spine Score (mSASSS). We assessed correlations with patient demographic characteristics (age, disease duration), disease activity (Bath AS Disease Activity Index [BASDAI], C-reactive protein level), and disease severity (mSASSS) using Spearman's rho. The independent association of VICM with 2-year radiographic progression, defined as a change of >0 in the mSASSS or the development of a new syndesmophyte, was analyzed by multivariate regression.
RESULTS: Levels of degraded VICM were significantly higher in both RA patients and AS patients than in healthy controls (both P<0.001). AS patients with the highest levels of VICM had the largest burden of disease (P<0.01), i.e., highest mSASSS score and BASDAI. VICM levels were significantly and independently associated with radiographic progression after 2 years (β=0.69, P=0.0005). Patients with both a high VICM level and a high baseline mSASSS had the highest risk of radiographic progression (odds ratio 13 for mSASSS change, 32 for new syndesmophytes), with progression occurring in 67% of these patients.
CONCLUSION: The present findings show that serum VICM may be of prognostic value in AS. The data also suggest that citrullination may be relevant in AS pathogenesis.

PMID: 23280360 [PubMed - indexed for MEDLINE]

The interferon type I signature towards prediction of non-response to rituximab in rheumatoid arthritis patients.

Arthritis Res Ther. 2012;14(2):R95

Authors: Raterman HG, Vosslamber S, de Ridder S, Nurmohamed MT, Lems WF, Boers M, van de Wiel M, Dijkmans BA, Verweij CL, Voskuyl AE

Abstract
INTRODUCTION: B cell depletion therapy is efficacious in rheumatoid arthritis (RA) patients failing on tumor necrosis factor (TNF) blocking agents. However, approximately 40% to 50% of rituximab (RTX) treated RA patients have a poor response. We investigated whether baseline gene expression levels can discriminate between clinical non-responders and responders to RTX.
METHODS: In 14 consecutive RA patients starting on RTX (test cohort), gene expression profiling on whole peripheral blood RNA was performed by Illumina® HumanHT beadchip microarrays. Supervised cluster analysis was used to identify genes expressed differentially at baseline between responders and non-responders based on both a difference in 28 joints disease activity score (ΔDAS28 < 1.2) and European League against Rheumatism (EULAR) response criteria after six months RTX. Genes of interest were measured by quantitative real-time PCR and tested for their predictive value using receiver operating characteristics (ROC) curves in an independent validation cohort (n = 26).
RESULTS: Genome-wide microarray analysis revealed a marked variation in the peripheral blood cells between RA patients before the start of RTX treatment. Here, we demonstrated that only a cluster consisting of interferon (IFN) type I network genes, represented by a set of IFN type I response genes (IRGs), that is, LY6E, HERC5, IFI44L, ISG15, MxA, MxB, EPSTI1 and RSAD2, was associated with ΔDAS28 and EULAR response outcome (P = 0.0074 and P = 0.0599, respectively). Based on the eight IRGs an IFN-score was calculated that reached an area under the curve (AUC) of 0.82 to separate non-responders from responders in an independent validation cohort of 26 patients using Receiver Operator Characteristics (ROC) curves analysis according to ΔDAS28 < 1.2 criteria. Advanced classifier analysis yielded a three IRG-set that reached an AUC of 87%. Comparable findings applied to EULAR non-response criteria.
CONCLUSIONS: This study demonstrates clinical utility for the use of baseline IRG expression levels as a predictive biomarker for non-response to RTX in RA.

PMID: 22540992 [PubMed - indexed for MEDLINE]

Clinical results for tocilizumab over one year in the clinical setting as assessed by CDAI (clinical disease activity index): CRP at week 12 and MMP-3 at week 24 are predictive factors for CDAI.

Rheumatol Int. 2012 Nov;32(11):3631-7

Authors: Kaneko A, Kida D, Saito K, Tsukamoto M, Sato T

Abstract
To investigate the clinical results of 1 year tocilizumab (TCZ) treatment of rheumatoid arthritis patients in clinical practice by using the clinical disease activity index (CDAI). Thirty-one patients with inadequate response to DMARDs, including methotrexate (MTX), or TNF inhibitors received TCZ (8 mg every 4 weeks). The clinical responses were measured using the 28-joint disease activity score (DAS28-ESR) and CDAI. Matrix metalloproteinase-3 (MMP-3) was assessed as a serological biomarker. Mean baseline DAS28-ESR was 5.96, decreasing to 2.89 at week 52 with a remission rate (DAS28-ESR < 2.6) of 35.5%. Mean baseline CDAI was 28.4, decreasing to 10.2 at week 52 with a remission rate (CDAI ≤ 2.8) of 22.6%. Of patients whose CRP levels had fallen to below the limit of detection by week 12, 65.2% achieved remission or low disease activity as assessed by CDAI at week 52. Median baseline MMP-3 level was 165.7 ng/mL, decreasing to 79.5 ng/mL at week 52. A positive correlation was seen between CDAI at week 52 and MMP-3 level from week 12 onward. About 50% of the patients treated with TCZ in clinical practice achieved a low disease activity level at week 52 as assessed by CDAI, which does not include acute-phase proteins. Our results suggested that CRP levels falling to below the limit of detection by week 12 and MMP-3 ≤ 80.6 ng/mL at week 24 could predict low disease activity or remission at week 52 as assessed by CDAI.

PMID: 22127466 [PubMed - indexed for MEDLINE]

ZAP-70+ B cell subset influences response to B cell depletion therapy and early repopulation in rheumatoid arthritis.

J Rheumatol. 2012 Dec;39(12):2276-85

Authors: Gremese E, Tolusso B, Fedele AL, Canestri S, Alivernini S, Ferraccioli G

Abstract
OBJECTIVE: To define the role of ZAP-70+ B cells (CD19+/ZAP-70+) as a biomarker of response to B cell depletion therapy (BCDT), their relationship with clinical outcome, and their behavior during repopulation of peripheral blood in patients with rheumatoid arthritis (RA).
METHODS: Thirty-one patients with RA underwent BCDT and were followed for 12 months. Disease activity was assessed with the European League Against Rheumatism (EULAR) criteria. Cytofluorimetric analysis of peripheral blood B cell subsets at baseline and at 6- and 12-month intervals after BCDT was performed using surface markers (CD45, CD3, CD56, CD19, IgD, CD38, CD27) and intracellular ZAP-70.
RESULTS: A moderate/good EULAR response was achieved in 66.6% of the RA cohort. The baseline percentage of CD19+/ZAP-70+ cells was lower in good responder patients (1.8% ± 1.7%) compared to poor responders (5.6% ± 4.9%; p = 0.02). A decrease of plasmablasts (IgD-CD27+CD38+) and pre-switch memory (IgD+CD27+) B cells occurred after BCDT. Recovery of B cells in peripheral blood after the first course of BCDT was characterized by the reappearance of B cell subtypes that showed a naive, activated phenotype, coupled with a decrease in memory cells. B cells carrying intracytoplasmic ZAP-70 increased significantly from the baseline value of 4.4% ± 4.5% to 12.4% ± 9.2% (p = 0.001) at the 6-month and to 9.4% ± 6.4% (p = 0.002) at the 12-month followup.
CONCLUSION: Baseline percentage of CD19+/ZAP-70+ cells is associated with the clinical outcome after BCDT in patients with RA. Depletion of plasmablasts and pre-switch memory B cells and increase of CD19+/ZAP-70+ cells are features of the recovery of the B cell pool after BCDT.

PMID: 22984268 [PubMed - indexed for MEDLINE]

Potential of ayurgenomics approach in complex trait research: leads from a pilot study on rheumatoid arthritis.

PLoS One. 2012;7(9):e45752

Authors: Juyal RC, Negi S, Wakhode P, Bhat S, Bhat B, Thelma BK

Abstract
BACKGROUND: Inconsistent results across association studies including Genome-wide association, have posed a major challenge in complex disease genetics. Of the several factors which contribute to this, phenotypic heterogeneity is a serious limitation encountered in modern medicine. On the other hand, Ayurveda, a holistic Indian traditional system of medicine, enables subgrouping of individuals into three major categories namely Vata, Pitta and Kapha, based on their physical and mental constitution, referred to as Prakriti. We hypothesised that conditioning association studies on prior risk, predictable in Ayurveda, will uncover much more variance and potentially open up more predictive health.
OBJECTIVES AND METHODS: Identification of genetic susceptibility markers by combining the prakriti based subgrouping of individuals with genetic analysis tools was attempted in a Rheumatoid arthritis (RA) cohort. Association of 21 markers from commonly implicated inflammatory and oxidative stress pathways was tested using a case-control approach in a total cohort comprising 325 cases and 356 controls and in the three subgroups separately. We also tested few postulates of Ayurveda on the disease characteristics in different prakriti groups using clinico-genetic data.
RESULTS: Inflammatory genes like IL1β (C-C-C haplotype, p=0.0005, OR=3.09) and CD40 (rs4810485 allelic, p=0.04, OR=2.27) seem to be the determinants in Vata subgroup whereas oxidative stress pathway genes are observed in Pitta (SOD3 rs699473, p=0.004, OR=1.83; rs2536512 p=0.005; OR=1.88 and PON1 rs662, p=0.04, OR=1.53) and Kapha (SOD3 rs2536512, genotypic, p=0.02, OR=2.39) subgroups. Fixed effect analysis of the associated markers from CD40, SOD3 and TNFα with genotype X prakriti interaction terms suggests heterogeneity of effects within the subgroups. Further, disease characteristics such as severity was most pronounced in Vata group.
CONCLUSIONS: This exploratory study suggests discrete causal pathways for RA etiology in prakriti based subgroups, thereby, validating concepts of prakriti and personalized medicine in Ayurveda. Ayurgenomics approach holds promise for biomarker discovery in complex diseases.

PMID: 23049851 [PubMed - indexed for MEDLINE]

Elevated serum resistin in juvenile idiopathic arthritis: relation to categories and disease activity.

J Clin Immunol. 2013 Jan;33(1):297-301

Authors: Gheita TA, El-Gazzar II, El Shazly RI, El-Din AM, Abdel-Rasheed E, Bassyouni RH

Abstract
BACKGROUND: Juvenile Idiopathic Arthritis (JIA) is one of the more common chronic diseases of childhood that often persists into adulthood and can result in significant long-term morbidity, including physical disability. The aim of the present study was to assess the serum level of resistin in JIA patients and compare its levels according to the categories, clinical manifestations and disease activity.
METHODS: Sixty-eight JIA patients and 33 age and sex matched control children were included in the present study. All patients included in this study were subjected to full history taking, clinical examination. Juvenile arthritis disease activity score in 27 joints (JADAS-27) was calculated and Childhood Health Assessment Questionnaire (CHAQ) was used to measure the functional status. Serum resistin levels were measured by enzyme-linked immunosorbent assay (ELISA).
RESULTS: The mean serum resistin was significantly higher in the JIA patients (4.01 ± 2.46 ng/ml) compared to the control (2.08 ± 1.23 ng/ml) (p<0.001) especially those with systemic-onset. Its level was significantly higher in those receiving steroids and those with a positive antinuclear antibody. Resistin significantly correlated with the JADAS27 (r 0.26, p 0.035) and CHAQ (r 0.4, p 0.001). The JIA patients were 50 females and 18 males; however, the level of resistin was insignificantly different according to the gender although there was a tendency to be higher in females.
CONCLUSION: Our results reinforce the proposition of an important role for resistin in JIA and may be considered an interesting biomarker for disease activity especially those with systemic onset.

PMID: 22886618 [PubMed - indexed for MEDLINE]

Is CDT truly a biomarker of disease activity in RA?

Z Rheumatol. 2012 Oct;71(8):717; author reply 717-8

Authors: Dhir V

PMID: 22968290 [PubMed - indexed for MEDLINE]

ACR/EULAR 2010 rheumatoid arthritis classification criteria.

Rheumatology (Oxford). 2012 Dec;51 Suppl 6:vi5-9

Authors: Kay J, Upchurch KS

Abstract
Advances in our understanding of the pathogenesis of RA over the past two decades, particularly the identification of cytokines that promote synovial inflammation (e.g. TNF-α, IL-1 and IL-6), have led to treatment courses that affect the disease process itself, beyond alleviation of symptoms. In turn, emphasis has shifted to intervention early enough in the disease course to prevent the joint destruction that follows inflammation. Accordingly, in 2010 the ACR and the European League Against Rheumatism (EULAR) put forward revised classification criteria emphasizing RA characteristics that emerge early in the disease course, including ACPAs, a biomarker that predicts aggressive disease. These were in contrast with the 1987 ARA criteria, which distinguished established RA patients from those with other forms of arthritis, and identified patients with later disease. The categories of the 2010 ACR/EULAR criteria are grouped into four classifications, with point scores for each: joint symptoms; serology (including RF and/or ACPA); symptom duration, whether <6 weeks or >6 weeks; and acute-phase reactants (CRP and/or ESR). The criteria were developed in a three-phase process, beginning with an analysis of patient cohorts to determine what disease characteristics had persuaded clinicians to initiate MTX therapy, followed by consensus-based decisions and the creation of a scoring system that would predict which patients would go on to develop persistent and/or erosive disease.

PMID: 23221588 [PubMed - indexed for MEDLINE]

High-sensitivity cardiac troponin-I is elevated in patients with rheumatoid arthritis, independent of cardiovascular risk factors and inflammation.

PLoS One. 2012;7(6):e38930

Authors: Bradham WS, Bian A, Oeser A, Gebretsadik T, Shintani A, Solus J, Estis J, Lu QA, Todd J, Raggi P, Stein CM

Abstract
OBJECTIVES: We examined the hypothesis that cardiac-specific troponin-I (cTn-I), a biomarker of myocardial injury, is elevated in patients with rheumatoid arthritis (RA).
BACKGROUND: RA patients have an increased incidence of heart failure (HF). Chronic myocardial injury in RA may be a mechanism for the development of HF.
METHODS: We compared cTn-I concentrations measured by high-sensitivity immunoassay in 164 patients with RA and 90 controls, excluding prior or active heart failure. We examined the relationship between cTn-I concentrations and cardiovascular risk factors, inflammation, and coronary artery calcium score (CACS), a measure of coronary atherosclerosis.
RESULTS: cTn-I concentrations were 49% higher in patients with RA (median 1.15 pg/mL [IQR 0.73-1.92] than controls (0.77 pg/mL [0.49-1.28](P<0.001). The difference remained statistically significant after adjustment for demographic characteristics (P = 0.002), further adjustment for cardiovascular (CV) risk factors (P = 0.004), inflammatory markers (P = 0.008), and in a comprehensive model of CV risk factors and inflammatory markers (P = 0.03). In patients with RA, cTn-I concentrations were positively correlated with age (rho = 0.359), Framingham risk score (FRS) (rho = 0.366), and systolic blood pressure (rho = 0.248 (all P values ≤ 0.001)), but not with measures of inflammation or RA drug therapies. cTn-I was significantly correlated with CACS in RA in univariate analysis, but not after adjustment for age, race, sex and FRS (P = 0.79). Further model adjustments for renal function and coronary artery disease confirmed the significance of the findings.
CONCLUSION: High-sensitivity cTn-I concentrations are elevated in patients with RA without heart failure, independent of cardiovascular risk profile and inflammatory markers. Elevated troponin concentrations in RA may indicate subclinical, indolent myocardial injury.

PMID: 22761714 [PubMed - indexed for MEDLINE]

Sensitivity and specificity of a point-of-care matrix metalloproteinase 9 immunoassay for diagnosing inflammation related to dry eye.

JAMA Ophthalmol. 2013 Jan;131(1):24-8

Authors: Sambursky R, Davitt WF, Latkany R, Tauber S, Starr C, Friedberg M, Dirks MS, McDonald M

Abstract
OBJECTIVES: To determine the clinical sensitivity, specificity, negative predictive value, and positive predictive value of a rapid point-of-care diagnostic test to detect elevated matrix metalloproteinase 9 levels (InflammaDry).
METHODS: In a prospective, sequential, masked, multicenter clinical trial, InflammaDry was performed on 206 patients: 143 patients with clinical signs and symptoms of dysfunctional tear syndrome (dry eyes) and 63 healthy individuals serving as controls. Participants were assessed as healthy controls or for a clinical diagnosis of dry eye using the Ocular Surface Disease Index, Schirmer tear test, tear breakup time, and keratoconjunctival staining.
MAIN OUTCOME MEASURES: The sensitivity and specificity of InflammaDry were compared with clinical assessment.
RESULTS: InflammaDry showed sensitivity of 85% (in 121 of 143 patients), specificity of 94% (59 of 63), negative predictive value of 73% (59 of 81), and positive predictive value of 97% (121 of 125).
CONCLUSION: Compared with clinical assessment, InflammaDry is sensitive and specific in diagnosing dry eye.
APPLICATION TO CLINICAL PRACTICE: Dry eye is often underdiagnosed resulting from poor communication between the clinical assessment of dry eye severity between clinicians and patients. This often leads to a lack of effective treatment. Matrix metalloproteinase 9 is an inflammatory biomarker that has been shown to be elevated in the tears of patients with dry eyes. The ability to accurately detect elevated matrix metalloproteinase 9 levels may lead to earlier diagnosis, more appropriate treatment, and better management of ocular surface disease. Preoperative and perioperative management of inflammation related to dry eyes may reduce dry eyes that develop after laser in situ keratomileusis, improve wound healing, and reduce flap complications. Recognition of inflammation may allow for targeted perioperative therapeutic management of care for patients who undergo cataract and refractive surgery and improve outcomes.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01313351.

PMID: 23307206 [PubMed - indexed for MEDLINE]

Germinal center kinase-like kinase (GLK/MAP4K3) expression is increased in adult-onset Still's disease and may act as an activity marker.

BMC Med. 2012;10:84

Authors: Chen DY, Chuang HC, Lan JL, Chen YM, Hung WT, Lai KL, Tan TH

Abstract
BACKGROUND: Germinal center kinase-like kinase (GLK, also termed MAP4K3), a member of the MAP4K family, may regulate gene transcription, apoptosis and immune inflammation in response to extracellular signals. The enhanced expression of GLK has been shown to correspond with disease severity in patients with systemic lupus erythematosus. We investigated the role of GLK in the pathogenesis of adult-onset Still's disease, which shares some similar clinical characteristics with systemic lupus erythematosus.
METHODS: The frequencies of circulating GLK-expressing T-cells in 24 patients with active adult-onset Still's disease and 12 healthy controls were determined by flow cytometry analysis. The expression levels of GLK proteins and transcripts were evaluated in peripheral blood mononuclear cells by immunoblotting and quantitative PCR. Serum levels of T helper (Th)17-related cytokines, including IL-1β, IL-6, IL-17 and TNF-α, were measured by ELISA.
RESULTS: Significantly higher median frequencies of circulating GLK-expressing T-cells were observed in patients with adult-onset Still's disease (31.85%) than in healthy volunteers (8.93%, P <0.001). The relative expression levels of GLK proteins and transcripts were also significantly higher in patients with adult-onset Still's disease (median, 1.74 and 2.35, respectively) compared with those in healthy controls (0.66 and 0.92, respectively, both P <0.001). The disease activity scores were positively correlated with the frequencies of circulating GLK-expressing T-cells (r = 0.599, P <0.005) and the levels of GLK proteins (r = 0.435, P <0.05) or GLK transcripts (r = 0.452, P <0.05) in patients with adult-onset Still's disease. Among the examined Th17-related cytokines, elevated levels of serum IL-6 and IL-17 were positively correlated with the frequencies of circulating GLK-expressing T-cells and the levels of GLK proteins as well as transcripts in patients with adult-onset Still's disease. GLK expression levels decreased significantly after effective therapy in these patients.
CONCLUSIONS: Elevated expression levels of GLK and their positive correlation with disease activity in patients with adult-onset Still's disease indicate that GLK may be involved in the pathogenesis and act as a novel activity biomarker of this disease.

PMID: 22867055 [PubMed - indexed for MEDLINE]

Serum hepcidin level is not an independent surrogate biomarker of disease activity or of radiographic progression in rheumatoid arthritis: results from the ESPOIR cohort.

Ann Rheum Dis. 2013 Feb;72(2):312-4

Authors: Sellam J, Kotti S, Fellahi S, Bastard JP, Meyer M, Lioté F, Meyer O, Simon T, Capeau J, Berenbaum F

PMID: 23148308 [PubMed - indexed for MEDLINE]

Forget personalised medicine and focus on abating disease activity.

Ann Rheum Dis. 2013 Jan;72(1):3-6

Authors: Smolen JS, Aletaha D

Abstract
In this viewpoint, we summarise three different lines of evidence suggesting that current biological therapies directed at different molecules or cells have similar efficacy in rheumatoid arthritis and target similar populations of patients; therefore, distinct biological effects of targeted therapies may not account for differences in response. Moreover, currently available individual biomarkers or multiple biomarker sets do not provide information beyond that conveyed by clinical disease activity. Smart and novel research designs will have to be developed to find pertinent biomarkers. Until then, the focus of clinicians may have to solely rest on clinical disease activity assessment and targeting remission or low disease activity rapidly.

PMID: 23136241 [PubMed - indexed for MEDLINE]

Oxidative stress as a potential biomarker for determining disease activity in patients with rheumatoid arthritis.

Free Radic Res. 2012 Dec;46(12):1482-9

Authors: Kundu S, Ghosh P, Datta S, Ghosh A, Chattopadhyay S, Chatterjee M

Abstract
Rheumatoid arthritis is an inflammatory, autoimmune disease where oxidative stress has been proposed to contribute to the joint tissue damage. To establish whether measurement of the redox status in blood mirrors the oxidant status at sites of inflammation in patients with rheumatoid arthritis, we concomitantly examined their oxidant status by spectrophotometry and/or flow cytometry. The basal levels of total reactive oxygen species (ROS), superoxide and hydroxyl radicals were significantly raised in neutrophils sourced from peripheral blood and synovial infiltrate, as also showed a strong positive correlation; however, there was no major increase in the reactive nitrogen species RNS generated in monocytes from both sources. Furthermore, raised levels of superoxide in neutrophils of synovial infiltrate showed a positive correlation with NADPH oxidase activity in synovial fluid. Additionally, as ROS generated in both peripheral blood and synovial infiltrate correlated positively with both DAS 28 and CRP/anti-CCP levels, its measurement can serve as an indirect measure of the degree of inflammation in patients with RA.

PMID: 22998065 [PubMed - indexed for MEDLINE]

Epigallocatechin-3-gallate modulates antioxidant and DNA repair-related proteins in exocrine glands of a primary Sjogren's syndrome mouse model prior to disease onset.

Autoimmunity. 2012 Nov;45(7):540-6

Authors: Ohno S, Yu H, Dickinson D, Chu TC, Ogbureke K, Derossi S, Yamamoto T, Hsu S

Abstract
The autoimmune disorder primary Sjogren's syndrome (SS) is associated with xerostomia and xerophthalmia. SS pathogenesis involves both genetic/epigenetic and environmental factors. A major potential contributor is oxidative stress associated with damage to cellular components, including DNA. We reported previously that the green tea polyphenol epigallocatechin-3-gallate (EGCG) normalizes the elevated levels of proliferating cell nuclear antigen (PCNA), a key component of DNA repair, in the NOD mouse model for SS and type 1 diabetes. The current study examined levels of the antioxidant enzymes peroxiredoxin 6 (PRDX6), catalase and superoxide dismutase (SOD), as well as PCNA, in NOD.B10.Sn-H2 mice, a model for primary SS, and determined the effect of EGCG on their expression. PCNA elevation was detected in the submandibular gland and pancreas by 8 weeks of age in water-fed mice, and increased through 14 weeks of age, prior to overt onset of symptoms. This early PCNA elevation was followed by a decline of peroxiredoxin 6 protein. In contrast, EGCG-fed mice exhibited normal levels of PCNA and peroxiredoxin 6, comparable to healthy untreated BALB/c mice. Similar patterns were observed in the pancreas, even though these mice do not develop diabetes. Thus, elevated PCNA is an early biomarker for exocrine glandular dysfunction associated with SS-like autoimmune disease, accompanied subsequently by decreased PRDX6 antioxidant enzyme levels that could further contribute to oxidative stress, and these changes precede inflammatory cell infiltration. Importantly, EGCG consumption normalizes the expression of these biomarkers in this model. These observations could lead to early diagnosis and intervention of autoimmune disorders.

PMID: 22849293 [PubMed - indexed for MEDLINE]

Characterization of a multiplex, 12-biomarker test for rheumatoid arthritis.

J Pharm Biomed Anal. 2012 Nov;70:415-24

Authors: Eastman PS, Manning WC, Qureshi F, Haney D, Cavet G, Alexander C, Hesterberg LK

Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disorder that primarily involves the joints. Accurate and frequent assessment of RA disease activity is critical to optimal treatment planning. A novel algorithm has been developed to determine a multi-biomarker disease activity (MBDA) score based upon measurement of the concentrations of 12 serum biomarkers in multiplex format. Biomarker assays from several different platforms were used in feasibility studies to identify biomarkers of potential significance. These assays were adapted to a multiplex platform for training and validation of the algorithm. In this study, the analytical performance of the underlying biomarker assays and the MBDA score was evaluated. Quantification of 12 biomarkers was performed with multiplexed sandwich immunoassays in three panels. Biomarker-specific capture antibodies were bound to specific locations in each well; detection antibodies were labeled with electrochemiluminescent tags. Data were acquired with a Sector Imager 6000, and analyte concentrations were determined. Parallelism, dynamic range, cross-reactivity, and precision were established for each biomarker as well as for the MBDA score. Interference by serum proteins, heterophilic antibodies, and common RA therapies was also assessed. The individual biomarker assays had 3-4 orders of magnitude dynamic ranges, with good reproducibility across time, operators, and reagent lots; the MBDA score had a median coefficient of variation of <2% across the score range. Cross-reactivity as well as interference by serum rheumatoid factor (RF), human anti-mouse antibodies (HAMA), or common RA therapies, including disease-modifying antirheumatic drugs and biologics, was minimal. The same MBDA score was observed in different subjects despite having different biomarker profiles, supporting prior literature reports that multiple pathways contribute to RA.

PMID: 22749821 [PubMed - indexed for MEDLINE]

Serum cotinine as a biomarker of tobacco exposure and the association with treatment response in early rheumatoid arthritis.

Arthritis Care Res (Hoboken). 2012 Dec;64(12):1804-10

Authors: Maska LB, Sayles HR, O'Dell JR, Curtis JR, Bridges SL, Moreland LW, Cofield SS, Mikuls TR

Abstract
OBJECTIVE: Cigarette smoking has emerged as a risk factor for the development of rheumatoid arthritis (RA). Recent studies have suggested that cigarette smoking may lead to lower treatment response rates with methotrexate (MTX) and some biologic agents in RA. Knowledge of whether tobacco exposure reduces treatment efficacy is important, since smoking could represent a modifiable factor in optimizing RA treatment.
METHODS: The study participants included patients with early RA (<3 years in duration) enrolled in the Treatment of Early Aggressive Rheumatoid Arthritis study, a randomized, blinded, placebo-controlled clinical trial comparing early intensive therapy (MTX + etanercept or MTX + hydroxychloroquine + sulfasalazine triple therapy) versus initial treatment with MTX with step-up to MTX + etanercept or to triple therapy if the disease was still active at 24 weeks. Serum cotinine was measured using a commercially available enzyme-linked immunosorbent assay at baseline and at 48 weeks, with detectable concentrations at both visits serving as an indicator of smoking status. The mean Disease Activity Score in 28 joints (DAS28) was compared by smoking status, adjusting for baseline disease activity.
RESULTS: Of the 412 subjects included in the analysis, 293 (71%) were categorized as nonsmokers and 119 (29%) as current smokers. There were no differences in the mean DAS28 score between 48 and 102 weeks based on smoking status for the overall group (P = 0.881) or by specific treatment assignment.
CONCLUSION: Among patients enrolled in a large randomized controlled trial of early RA with poor prognostic factors, smoking status did not impact treatment responses for those receiving early combination or initial MTX with step-up therapy at 24 weeks if the disease was still active.

PMID: 22730343 [PubMed - indexed for MEDLINE]