Novel Biomarker Of Disease Activity Research Articles

Quantitative Proteomic Profile of Psoriatic Epidermis Identifies OAS2 as a Novel Biomarker for Disease Activity.

Psoriasis is a common chronic inflammatory systemic disease. Epidermal proteins are considered to be important in maintaining skin barrier function, innate immunity, and inflammation. To define more possible roles of the epidermis in the pathogenesis of psoriasis, quantified proteomic analysis was used to screen and analyze the differentially expressed epidermal proteins between 16 psoriasis patients and 15 healthy controls. Upregulated differential expression proteins (DEPs) include several significant functional protein clusters, including antimicrobial peptides (AMPs) and antiviral proteins (AVPs). The levels of 2–5-oligoadenylate synthase 2 (OAS2) in both epidermis and serum levels were significantly elevated in psoriasis and were also positively correlated with Psoriasis Area Severity Index (PASI) scores and Body Surface Area (BSA) scores. Moreover, OAS2 expression in psoriatic skin significantly decreased after IL-17R mono-antibody treatment. It has been clarified that inflamed keratinocytes were the main source of abnormally increased OAS2 in psoriasis skin by immunofluorescence and primary cell cultures. Keratinocyte-derived OAS2 can be induced by not only IFNβ, but also psoriasis associated cytokines like IL-17A and IL-6. This study revealed that AMPs and AVPs are two important functional protein clusters altering innate immune in psoriatic epidermis. OAS2 is a novel potential sensitive biomarker, which could predict the severity and activity of psoriasis, and could also be used as an indicator to evaluate or monitor the efficacy of clinical treatment.

Serum sTREM-1 in adult-onset Still's disease: a novel biomarker of disease activity and a potential predictor of the chronic course.

ObjectivesTriggering receptor expressed on myeloid cells-1 (TREM-1) is an amplifier of inflammatory signals. Recently, a soluble form of TREM-1 (sTREM-1) was described. This study aimed to investigate the role of serum sTREM-1 in patients with adult-onset Still’s disease (AOSD).MethodsSerum sTREM-1 levels were detected in 108 AOSD patients, 88 RA patients and 112 healthy controls (HC). The correlations of sTREM-1 with disease activity, clinical characteristics and laboratory parameters in AOSD patients were analysed by the Spearman correlation test. Risk factors for the chronic course of AOSD were evaluated by multivariate logistic regression analysis.ResultsAOSD patients had significantly higher serum sTREM-1 levels than RA patients and HC, and serum sTREM-1 levels were correlated with the systemic score, ferritin, leucocyte count, CRP, IL-1β and IL-6. The elevation in the initial sTREM-1 level by itself could discriminate patients developing the chronic course from patients developing the nonchronic course. Moreover, an elevated sTREM-1 level (> 526.4475 pg/ml) was an independent risk factor for the chronic course in active AOSD patients. Furthermore, interfering with TREM-1 engagement led to reductions in the secretion of pro-inflammatory cytokines, such as IL-1β, IL-6 and TNF-α, in neutrophils and monocytes from active AOSD patients.ConclusionSerum sTREM-1 levels are correlated with disease activity, and an elevation in the initial serum sTREM-1 level is a potential predictor of the chronic course in AOSD patients, which currently provides the best predictive model for identifying patients prone to developing the chronic course of AOSD.

Evaluation of Potential Serum Biomarkers of Disease Activity in Diverse Forms of Vasculitis.

We evaluated potential circulating biomarkers of disease activity in giant cell arteritis (GCA), Takayasu arteritis (TA), polyarteritis nodosa (PAN), and eosinophilic granulomatosis with polyangiitis (EGPA). A panel of 22 serum proteins was tested in patients enrolled in the Vasculitis Clinical Research Consortium Longitudinal Studies of GCA, TA, PAN, or EGPA. Mixed models were used for most analyses. A J48 classification tree method was used to find the most relevant markers to differentiate between active and inactive GCA. Tests were done on 418 samples from 152 patients (60 GCA, 29 TA, 26 PAN, 37 EGPA), during both active vasculitis and remission. In GCA, these showed significant (p < 0.05) differences between disease states: B cell-attracting chemokine 1 (BCA)-1/CXC motif ligand 13 (CXCL13), erythrocyte sedimentation rate (ESR), interferon-γ-induced protein 10/CXC motif chemokine 10, soluble interleukin 2 receptor α (sIL-2Rα), and tissue inhibitor of metalloproteinase-1 (TIMP-1). In EGPA, these showed significant increases during active disease: granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage-CSF, interleukin (IL)-6, IL-15, and sIL-2Rα. BCA-1/CXCL13 also showed such increases, but only after adjustment for treatment. In PAN, ESR and matrix metalloprotease (MMP)-3 showed significant differences between disease states. Differences in biomarker levels between diseases were significant for 11 markers and were more striking (all p < 0.01) than differences related to disease activity. A combination of lower values of TIMP-1, IL-6, interferon-γ, and MMP-3 correctly classified 87% of samples with inactive GCA. We identified novel biomarkers of disease activity in GCA and EGPA. Differences of biomarker levels between diseases, independent of disease activity, were more apparent than differences related to disease activity. Further studies are needed to determine whether these serum proteins have potential for clinical use in distinguishing active disease from remission or in predicting longer-term outcomes.

Circular RNAS: novel biomarkers of disease activity in systemic lupus erythematosus?

Circular RNAs (circRNAs) are a class of non-coding RNAs that regulate gene expression by acting as competitive endogenous RNAs (ceRNAs) and modulating gene transcription. Several studies support the implication of circRNAs in a variety of human diseases, but research on the role of circRNAs in systemic lupus erythematosus (SLE) is lacking. In a study recently published in Clinical Science (2018), Zhang et al. identified hsa_circ_0012919 as a potential biomarker of disease activity in SLE patients. The authors observed different circRNA expression between SLE patients and healthy controls, an association with clinical variables and with the abnormal DNA methylation present in SLE CD4+ T cells. Finally, Zhang et al. demonstrated that hsa_circ_0012919 acts as a miRNA sponge for miR-125a-3p, regulating the gene expression of targets RANTES and KLF13 that are involved in the physiology and pathophysiology of acute and chronic inflammatory processes. These findings support the role of circRNAs in the pathophysiology of SLE.

Sa1761 – Chitinase 3-Like-1 Protein: A Novel Biomarker of Disease Activity and Risk of Relapse in Children with Inflammatory Bowel Disease

Sa1761 – Chitinase 3-Like-1 Protein: A Novel Biomarker of Disease Activity and Risk of Relapse in Children with Inflammatory Bowel Disease

The Micro-RNA Expression Profiles of Autoimmune Arthritis Reveal Novel Biomarkers of the Disease and Therapeutic Response.

Rheumatoid arthritis (RA) is a chronic autoimmune disease of the joints affecting about 0.3–1% of the population in different countries. About 50–60 percent of RA patients respond to presently used drugs. Moreover, the current biomarkers for RA have inherent limitations. Consequently, there is a need for additional, new biomarkers for monitoring disease activity and responsiveness to therapy of RA patients. We examined the micro-RNA (miRNA) profile of immune (lymphoid) cells of arthritic Lewis rats and arthritic rats treated with celastrol, a natural triterpenoid. Experimental and bioinformatics analyses revealed 8 miRNAs (miR-22, miR-27a, miR-96, miR-142, miR-223, miR-296, miR-298, and miR-451) and their target genes in functional pathways important for RA pathogenesis. Interestingly, 6 of them (miR-22, miR-27a, miR-96, miR-142, miR-223, and miR-296) were further modulated by celastrol treatment. Interestingly, serum levels of miR-142, miR-155, and miR-223 were higher in arthritic versus control rats, whereas miR-212 showed increased expression in celastrol-treated rats compared with arthritic rats or control rats. This is the first study on comprehensive miRNA expression profiling in the adjuvant-induced arthritis (AA) model and it also has revealed new miRNA targets for celastrol in arthritis. We suggest that subsets of the above miRNAs may serve as novel biomarkers of disease activity and therapeutic response in arthritis.

Serum calreticulin as a novel biomarker of juvenile idiopathic arthritis disease activity.

This study aimed to investigate the relations between calreticulin (CRT) serum level and both disease activity and severity parameters in juvenile idiopathic arthritis (JIA). In this study, 60 children with JIA and 50 age-and-sex-matched healthy subjects were enrolled. The assessment of the disease activity was done using juvenile arthritis disease activity score 27 (JADAS-27). The assessment of disease severity was done via gray-scale ultrasonography (US) and power Doppler US (PDUS). Enzyme-linked immunosorbent assay (ELISA) was used to assay the serum level of human CRT. The mean serum CRT levels in JIA patients was 8.6±1.2 ng/mL and showed a highly significant increase (p=0.001) as compared to the mean serum levels in the controls (5.02±0.77 ng/mL). There were statistically significant positive correlations between the serum CRT levels and disease duration, tender joint count, swollen joint count, visual analog scale, erythrocyte sedimentation rate, JADAS-27, C-reactive protein, rheumatoid factor titer, and ultrasonographic grading for synovitis and neovascularization. Elevated serum CRT levels in JIA patients and its correlations with JIA disease activity and severity parameters signified that CRT might be used as a novel biomarker for disease activity and severity in JIA.

Insulin-like growth factor binding protein-2 as a novel biomarker for disease activity and renal pathology changes in lupus nephritis.

Lupus nephritis (LN) is one of the most serious manifestations of systemic lupus erythematosus. Invasive renal biopsy remains the gold standard for the diagnosis and management of LN. The objective of this study is to validate serum insulin-like growth factor binding protein-2 (IGFBP-2) as a novel biomarker for clinical disease and renal pathology in LN. Eighty-five biopsy-proven lupus nephritis patients, 18 chronic kidney disease (CKD) patients and 20 healthy controls were recruited for enzyme-linked immunosorbent assay (ELISA) testing of serum IGFBP-2 levels. Compared to CKD patients of origins other than lupus or healthy controls, serum IGFBP-2 levels were elevated significantly in LN patients. Serum IGFBP-2 was able to discriminate LN patients from the other two groups of patients [area under the curve (AUC) = 0·65, 95% confidence interval (CI) = 0·52-0·78; P = 0·043 for LN versus CKD; 0·97, 95% CI = 0·93-1·00; P < 0·0001 for LN versus healthy controls]. Serum IGFBP-2 was a potential indicator of both global disease activity and renal disease activity in LN patients, correlated with serum creatinine levels (r = 0·658, P < 0·001, n = 85) and urine protein-to-creatinine levels (r = 0·397, P < 0·001, n = 85). More importantly, in 19 concurrent patient samples, serum IGFBP-2 correlated with the chronicity index of renal pathology (r = 0·576, P = 0·01, n = 19) but not renal pathological classification. In conclusion, serum IGFBP-2 is a promising biomarker for lupus nephritis, reflective of disease activity and chronicity changes in renal pathology.

Circulating YKL‐40 in myelofibrosis a potential novel biomarker of disease activity and the inflammatory state

Chronic myeloproliferative neoplasms (MPN), encompassing essential thrombocythaemia (ET), polycythaemia vera (PV) and myelofibrosis (PMF), are featured by a chronic inflammatory state which is pronounced in myelofibrosis The value of YKL-40 as a biomarker of disease burden has been demonstrated in several different diseases, including cancer, diabetes mellitus and cardiovascular diseases. A state of chronic inflammation is shared by them all, YKL-40 also being involved in the severity of chronic endothelial inflammation, which today is considered of crucial importance for the development of atherosclerosis. The MPNs being cancers with a heavy burden of cardiovascular diseases we hypothesised that circulating YKL-40 might reflect the inflammatory process and potentially serve as a novel disease marker. Using ELISA, we measured YKL-40 in 15 patients with ET, 16 patients with PV, 17 patients with PMF and 30 healthy controls. YKL-40 was significantly elevated in PMF vs. control subjects, PMF levels median 43 ng/mL vs. controls median 28 ng/mL, P = 0.033. An increase from ET over PV may reflect the integrated impact of disease processes in MPNs.

18F-Sodium Fluoride Uptake Is a Marker of Active Calcification and Disease Progression in Patients With Aortic Stenosis

18F-Sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) are promising novel biomarkers of disease activity in aortic stenosis. We compared 18F-NaF and 18F-FDG uptake with histological characterization of the aortic valve and assessed whether they predicted disease progression. Thirty patients with aortic stenosis underwent combined positron emission and computed tomography using 18F-NaF and 18F-FDG radiotracers. In 12 patients undergoing aortic valve replacement surgery (10 for each tracer), radiotracer uptake (mean tissue/ =0.65; P=0.04) and osteocalcin (r=0.68; P=0.03) immunohistochemistry. There was no significant correlation between 18F-FDG uptake and CD68 staining (r=-0.43; P=0.22). After 1 year, aortic valve calcification increased from 314 (193-540) to 365 (207-934) AU (P<0.01). Baseline 18F-NaF uptake correlated closely with the change in calcium score (r=0.66; P<0.01), and this improved further (r=0.75; P<0.01) when 18F-NaF uptake overlying computed tomography-defined macrocalcification was excluded. No significant correlation was noted between valvular 18F-FDG uptake and change in calcium score (r=-0.11; P=0.66). 18F-NaF uptake identifies active tissue calcification and predicts disease progression in patients with calcific aortic stenosis. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01358513.

Changes in novel biomarkers of disease activity in juvenile and adult dermatomyositis are sensitive biomarkers of disease course

Muscle enzyme levels are insensitive markers of disease activity in juvenile and adult dermatomyositis (DM), especially during the active treatment phase. To improve our ability to monitor DM disease activity longitudinally, especially in the presence of immunomodulating agents, we prospectively evaluated whether interferon (IFN)-dependent peripheral blood gene and chemokine signatures could serve as sensitive and responsive biomarkers for change in disease activity in adult and juvenile DM. Peripheral blood and clinical data were collected from 51 patients with juvenile or adult DM prospectively over 2 study visits. We performed disease activity measurements and calculated whole-blood type I IFN gene and chemokine scores. We also measured serum levels of other proinflammatory cytokines, including interleukin-6 (IL-6). Changes in juvenile and adult DM global disease activity correlated positively and significantly with changes in the type I IFN gene score before adjustment for medication use (r = 0.33, P = 0.023) and with changes in the IFN chemokine score before and after adjustment for medication use (r = 0.53, P < 0.001 and r = 0.50, P < 0.001, respectively). Changes in muscle and extramuscular visual analog scale (VAS) scores correlated positively with changes in IFN gene and chemokine scores (P = 0.002, P < 0.001, P = 0.095, P < 0.001). Serum levels of IL-6, IL-8, and tumor necrosis factor α (TNFα) correlated positively with changes in global, muscle, and extramuscular VAS scores (P < 0.05). Our findings suggest that changes in type I IFN gene and chemokine scores as well as in levels of IL-6, IL-8, and TNFα may serve as sensitive and responsive longitudinal biomarkers of change in disease activity in juvenile and adult DM, even in the presence of immunomodulating agents.

Circulating anti-double-stranded DNA antibody-secreting cells in patients with systemic lupus erythematosus: a novel biomarker for disease activity

Antibodies against double-stranded DNA (dsDNA) are widely used to diagnose systemic lupus erythematosus (SLE) and evaluate its activity in patients. This study was undertaken to examine the clinical utility of circulating anti-dsDNA antibody-secreting cells for evaluating SLE patients. Anti-dsDNA antibody-secreting cells quantified using an enzyme-linked immunospot assay were detected in the spleen, bone marrow and peripheral blood from MRL/lpr but not in control BALB/c mice. Circulating anti-dsDNA antibody-secreting cells were detected in 29 (22%) of 130 patients with SLE, but in none of 49 with non-SLE connective-tissue disease or 18 healthy controls. The presence of circulating anti-dsDNA antibody-secreting cells was associated with persistent proteinuria, high SLE disease activity index and systemic lupus activity measures, and a high serum anti-dsDNA antibody titre measured with an enzyme-linked immunosorbent assay. The positive predictive value for active disease was 48% for circulating anti-dsDNA antibody-secreting cells versus 17% for serum anti-dsDNA antibodies. A prospective cohort of patients with circulating anti-dsDNA antibodies and inactive SLE showed that the cumulative disease flare-free rate was significantly lower in patients with than without circulating anti-dsDNA antibody-secreting cells (p < 0.001). Circulating anti-dsDNA antibody-secreting cells are a useful biomarker for assessing disease activity in SLE patients.

Faecal chitinase 3-like-1: a novel biomarker of disease activity in paediatric inflammatory bowel disease

Chitinase 3-like-1 (CHI3L1) is up-regulated in the inflamed mucosa of inflammatory bowel disease (IBD). To evaluate the usefulness of a faecal CHI3L1 assay, as a reliable marker for predicting the severity of paediatric IBD. Faecal samples were obtained from ulcerative colitis (UC, n = 94), Crohn's disease (CD, n = 87), and healthy individuals (n = 56). The faecal CHI3L1 and calprotectin levels were determined by ELISA. For endoscopic evaluation, the sum of the Matts' score for UC and the simple endoscopic score for CD (SES-CD) were used. Ileal lesions were evaluated by ultrasonography. Faecal CHI3L1 levels were significantly elevated in active UC (median 366.6 ng/g, n = 44) and active CD (median 632.7 ng/g, n = 48) patients, as compared with healthy individuals (median 2.2 ng/g, n = 56). In UC patients, the faecal CHI3L1 levels were positively correlated with the sum of the Matts' score (r = 0.73, P < 0.01, n = 42). In CD patients, there was a significant correlation between faecal CHI3L1 levels and endoscopic activity as determined by the SES-CD scoring system (r = 0.61, P < 0.01, n = 25). The faecal CHI3L1 levels of patients with wall thickening of their small intestine were significantly higher than those of healthy controls or patients without wall thickening. The cutoff value of 13.7 ng/g for fecal CHI3L1(the 95th percentile of the control value) predicted active lesions in IBD patients with a sensitivity of 84.7% and a specificity of 88.9%. Faecal CHI3L1 assays may be useful for predicting the severity and activity of mucosal inflammation in IBD.

Whole-blood transcriptional profiling of interferon-inducible genes identifies highly upregulated IFI27 in primary myelofibrosis

Gene expression profiling studies have unraveled deregulation of several genes that might be of pathogenetic importance for the development and phenotype of the Philadelphia-negative chronic myeloproliferative neoplasms. In the context of interferon-alpha2 as a promising therapeutic agent, we focused upon the transcriptional profiling of interferon-associated genes in patients with essential thrombocythemia (ET) (n = 19), polycythemia vera (PV) (n = 41), and primary myelofibrosis (PMF) (n = 9). Using whole-blood transcriptional profiling and accordingly obtaining an integrated signature of genes expressed in several immune cells (granulocytes, monocytes, B cells, T cells, platelets), we have identified a number of interferon-associated genes to be significantly deregulated but with a highly significant deregulation of interferon-inducible gene 27 (IFI27) (ET, PV, and PMF, fold change 8, 16, and 30, respectively). The striking deregulation of IFI genes may reflect a hyperstimulated but insufficient immune system being most enhanced in patients with advanced myelofibrosis, in whom the IFI27 gene displayed an exceedingly high expression. The interferon signature may reflect primary myelofibrosis as the burn-out phase of chronic inflammation which ultimately elicits clonal evolution and expansion owing to an exaggerated but incompetent antitumor immune response. Finally, IFI27 may be a novel biomarker of disease activity and tumor burden in patients with CMPNs.

Plasma Ghrelin Paradoxically Rises Upon Feeding in Active Crohn's Disease

Introduction Ghrelin is an orexigenic hormone. Circulating levels normally rise between episodes of food ingestion and then fall upon eating. Ghrelin may also be a signal to prime the gut for nutrient absorption. An anti-inflammatory role has also been proposed. A single previous report has suggested an increase in plasma fasting acylated ghrelin expression in active inflammatory bowel disease (IBD), with levels returning to normal once the disease is in remission. The postprandial response of ghrelin in intestinal inflammation has never been described. Methods 21 patients with active Crohn9s disease (CD) and 12 healthy controls were recruited. Disease activity was classified through independent histopathological/endoscopic assessments, validated patient questionnaires and biochemical scores. Gut hormone responses to a mixed nutrient test meal were studied using a multiplex ELISA technique (Luminex). Patient symptoms were assessed using a validated visual analogue score (VAS). A subgroup of patients who achieved remission (without surgery or anti-TNFα treatment) was also re-studied later. Results CD patients with active inflammation displayed a ∼6-fold significant reduction in basal appetite parameters as measured by VAS (p A significant correlation (p = 0.019) was noted between the total acetylated ghrelin secreted and the Crohn9s Disease Activity Index. A significant correlation also existed between ghrelin secretion and stool frequency (p = 0.01), more so in the SB CD group (p = 0.004). There was a significant negative correlation noted between the abdominal pain scores in the visual analogue score specifically in the SB CD group (p = 0.0008). After treatment of CD, the VAS reverted to those of normal controls and ghrelin responses to the test meal now showed a postprandial fall, as expected physiologically. Conclusion Ghrelin levels show an unexpected rise in response to a test meal in ileal CD. Ghrelin is not expressed in the healthy distal small bowel. It is now necessary to explore whether inflammation induces its expression there, or whether gastric secretion of ghrelin is somehow amplified at a distance. In intestinal inflammation, it may be that ghrelin assumes more its secondary role, that of an anti-inflammatory peptide. This plays a protective role when the antigen load of a meal is presented to the inflamed gut. The changes noted after treatment tend to corroborate this. Its postprandial response may also present a useful novel biomarker of disease activity.

Plasma Ghrelin paradoxically rises upon feeding in active Crohn's disease

IntroductionGhrelin is an orexigenic hormone. Circulating levels normally rise between episodes of food ingestion and then fall upon eating. Ghrelin may also be a signal to prime the gut for...

Serum proteome changes in acromegalic patients following transsphenoidal surgery: novel biomarkers of disease activity

Transsphenoidal adenomectomy is the primary treatment for acromegaly. However, assessment of the therapeutical outcome remains problematic since the existing biomarkers of disease activity frequently show discordant results. To discover novel serum biomarkers of disease activity in acromegalic patients before and after surgery. Serum samples of eight newly diagnosed acromegaly patients before and after transsphenoidal surgery were analyzed for proteomic changes by two-dimensional gel electrophoresis. Protein spots displaying statistically significant changes, pre- versus post-surgery, were identified by mass spectrometry (MS), tandem MS (MS/MS), and western blot analysis. Six protein spots displaying decreased intensities after surgery were identified as transthyretin (two isoforms), haptoglobin α2, β-hemoglobin, and apolipoprotein A-1 (two isoforms). One protein spot, identified as complement C4B precursor, was increased after the surgery. Seven serum protein spots were differentially expressed following surgery in acromegalic patients. The identified proteins represent potential novel biomarkers to assess the effectiveness of surgical treatment in acromegalic individuals. Future studies will validate the use of the identified proteins as biomarkers of disease activity after medical treatment of acromegaly.

Urinary neutrophil gelatinase-associated lipocalin as a novel biomarker for disease activity in lupus nephritis

Clinical and laboratory markers in current use have limited specificity and sensitivity for predicting the development of renal disease in lupus patients. In this longitudinal study, we investigated whether urinary neutrophil gelatinase-associated lipocalin (uNGAL) predicts active nephritis and renal flares in lupus patients with and without a history of biopsy-proven lupus nephritis. Renal disease activity and flare status was determined by SLEDAI and BILAG scores. Random effects models were used to determine whether uNGAL was a significant predictor for renal disease activity in SLE patients, and for renal flares in patients with established nephritis. To assess the predictive performance of uNGAL, receiver operating characteristic (ROC) curves were constructed using the previous visit's uNGAL level. These curves were then compared with curves constructed with currently used biomarkers. Cut-offs determined by ROC curves were tested in an independent validation cohort. uNGAL was found to be a significant predictor of renal disease activity in all SLE patients, and a significant predictor for flare in patients with a history of biopsy-proven nephritis, in multivariate models adjusting for age, race, sex and anti-double-stranded (ds)DNA antibody titres. As a predictor of renal flare in patients with biopsy-proven nephritis, uNGAL outperformed anti-dsDNA antibody titres. These results were confirmed in an independent validation cohort. uNGAL predicts renal flare in patients with a history of biopsy-proven nephritis with high sensitivity and specificity. Furthermore, uNGAL is a more sensitive and specific forecaster of renal flare in patients with a history of lupus nephritis than anti-dsDNA antibody titres.

Potential novel biomarkers of disease activity in rheumatoid arthritis patients: CXCL13, CCL23, transforming growth factor α, tumor necrosis factor receptor superfamily member 9, and macrophage colony‐stimulating factor

To determine whether the plasma levels of a range of inflammatory proteins have utility as biomarkers of disease activity in rheumatoid arthritis (RA) patients. Plasma proteins (n = 163) were profiled in 44 patients with RA diagnosed according to the American College of Rheumatology 1987 criteria (22 with active and 22 with quiescent disease) and in 16 age- and sex-matched healthy controls. The utility of a subset of differentially expressed proteins as predictors of RA disease activity was investigated using partial least-squares discriminant analysis, and their response to therapeutic intervention was evaluated in plasma from an additional cohort of 16 patients with active RA treated with anti-tumor necrosis factor alpha (anti-TNFalpha). The protein profiling study identified 25 proteins that were differentially expressed in plasma samples from patients with active RA (P for the false discovery rate < or = 0.01) compared with those with quiescent RA, including the previously described interleukin-6 (IL-6), oncostatin M, and IL-2, and the 5 less-established markers macrophage colony-stimulating factor (M-CSF), tumor necrosis factor receptor superfamily member 9, CCL23, transforming growth factor alpha, and CXCL13. Systemic levels of these 5 markers correlated with the C-reactive protein level, erythrocyte sedimentation rate, rheumatoid factor level, tender joint count in 68 joints, and Disease Activity Score in 28 joints (DAS28), and their combined plasma levels were shown to be good predictors of disease activity (kappa = 0.64). In anti-TNFalpha-treated RA patients, plasma levels of CXCL13 were reduced after 1 and 7 days of therapy, and levels of CCL23, M-CSF, and CXCL13 showed a statistically significant positive correlation with the DAS28 score. This exploratory study for biomarker discovery led to the identification of several proteins predictive of RA disease activity that may be useful in the definition of disease subphenotypes and in the measurement of response to therapy in clinical studies.