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Objectives: Measurement of serum biomarkers at disease onset may improve prediction of disease course in patients with early rheumatoid arthritis (RA). We evaluated the multi-biomarker disease activity (MBDA) score and early changes in MBDA score for prediction of 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) remission and radiographic progression in the double-blinded OPERA trial.Method: Treatment-naïve RA patients (N = 180) with moderate or high DAS28 were randomized to methotrexate (MTX) + adalimumab (n = 89) or MTX + placebo (n = 91) in combination with glucocorticoid injection into swollen joints. X-rays of hands and feet were evaluated at months 0 and 12 (n = 164) by the total Sharp van der Heijde score (TSS). The smallest detectable change (1.8 TSS units) defined radiographic progression (∆TSS ≥ 2). Clinical remission (DAS28-CRP < 2.6) was assessed at baseline and 6 months. MBDA score was determined at 0 and 3 months and tested in a multivariable logistic regression model for predicting DAS28 remission at 6 months and radiographic progression at 1 year.Results: Baseline MBDA score was independently associated with radiographic progression at 1 year [odds ratio (OR) = 1.03/unit, 95% confidence interval (CI) = 1.01-1.06], and changes in MBDA score from baseline to 3 months with clinical remission at 6 months [OR = 0.98/unit, 95% CI 0.96-1.00). In anti-cyclic citrullinated peptide antibody (anti-CCP)-positive patients, 35 of 89 with high MBDA score (> 44) showed radiographic progression (PPV = 39%), compared with 0 of 15 patients (NPV = 100%) with low/moderate MBDA score (≤ 44) (p = 0.003).Conclusion: Early changes in MBDA score were associated with clinical remission based on DAS28-CRP at 6 months. In anti-CCP-positive patients, a non-high baseline MBDA score (≤ 44) had a clinical value by predicting very low risk of radiographic progression at 12 months. [ABSTRACT FROM AUTHOR]

A large-scale mathematical model, the Entelos® Rheumatoid Arthritis (RA) PhysioLab® platform, has been developed to describe the inflammatory and erosive processes in afflicted joints of people suffering from RA. The platform represents the life cycle of inflammatory cells, endothelium, synovial fibroblasts, and chondrocytes, as well as their products and interactions. The interplay between these processes culminates in clinically relevant measures for inflammation and erosion. The simulation model is deterministic, which allows tracing back the mechanism of action for a particular simulation result. Different patient phenotypes are represented by different virtual patients. The RA PhysioLab platform has been used to systematically and quantitatively study the predicted therapeutic effect of modulating several molecular targets, which resulted in a ranking of putative drug targets and a workflow to confirm the simulations experimentally. In addition, critical pathways were identified that drive the predicted disease outcome. Within these pathways, targets were identified from public literature that were not previously associated with arthritis. The model provides insights into the biology of RA and can be used as a platform for hypothesis-driven research. Case studies of therapies directed against IL-12 and IL-15 illustrate the approach, with emphasis on the analysis of system dynamics. [ABSTRACT FROM AUTHOR]

Introduction: Receptor activator of nuclear factor kappa B ligand (RANKL) is a key regulator of bone metabolism. Anti-citrullinated protein antibodies (ACPA) have been suggested to cause bone destruction by osteoclast activation. We investigated the relationship between RANKL and ACPA in patients with early untreated rheumatoid arthritis (RA)., Methods: Patients with newly diagnosed untreated RA (n = 183) were analyzed at baseline and 3 months after initiating methotrexate (MTX) treatment. Serum RANKL (total RANKL), ACPA (anti-CCP2) and ACPA specificities (anti-citrullinated (cit)-vimentin, anti-cit-enolase and anti-cit-fibrinogen) were determined by enzyme-linked immunosorbent assay (ELISA). Synovial RANKL expression was evaluated by immunohistochemistry in a small group of patients (n = 15). The relationship between anti-cit-vim antibodies and bone destruction was further validated in 1116 RA patients included in the EIRA cohort. Pearson's chi-square test, Wilcoxon rank sum test, Wilcoxon signed rank test and linear regression models were used., Results: Serum RANKL concentration was significantly higher (p <0.05) in ACPA-positive (median: 689 pmol/L, IQR 342-1253) compared with ACPA-negative (median: 159 pmol/L, IQR 96-243) patients and this difference was also seen for synovial RANKL expression. Serum RANKL associated with ACPA (p <0.05) and bone erosions in rheumatoid factor (RF)-negative patients (n = 59). Among ACPA specificites, anti-cit-vimentin (amino acids 60-75) was associated with higher RANKL concentration and higher prevalence of bone erosion (p <0.05). Significant reductions in both serum RANKL and ACPA levels were observed after 3 months of MTX treatment (p <0.05)., Conclusions: RANKL was elevated in ACPA-positive and in anti-cit-vimentin-positive patients with early untreated RA and associated with bone erosions. These findings give further support for an early direct pathogenic link between ACPA and bone destruction in RA.

Objectives: To assess the ability of a multi-biomarker disease activity (MBDA) score to track clinical response in patients with rheumatoid arthritis (RA) treated with different TNF inhibitors., Methods: The study included 147 patients who had received adalimumab, etanercept, or infliximab for a year or more, during routine clinical care at the University Hospital of Occupational and Environmental Health, Japan. MBDA scores and clinical measures of disease activity were evaluated at baseline and, after 24 weeks (N = 84) and 52 weeks of treatment. Relationships between the changes (∆) in MBDA score and changes in clinical measures or EULAR response categories were evaluated., Results: The median disease activity was 5.7 by DAS28-ESR and 64 by MBDA score at baseline, and decreased significantly with treatment. ∆MBDA scores over 1 year correlated with ∆DAS28-ESR (r = 0.48) and ∆DAS28-CRP (r = 0.46). Linear relationships between ∆MBDA scores and ∆DAS28-ESR or ∆DAS28-CRP were not significantly different between TNF inhibitors. The MBDA scores declined significantly more in good responders (median change: -29) than moderate (-21), and more in moderate than in non-responders (+ 2), by the EULAR criteria., Conclusions: MBDA scores tracked disease activity and treatment response in patients with RA treated with three TNF inhibitors. The relationships between ∆MBDA scores and ∆DAS28-ESR or ∆DAS28-CRP were consistent across the three TNF inhibitor groups.

A large-scale mathematical model, the Entelos Rheumatoid Arthritis (RA) PhysioLab platform, has been developed to describe the inflammatory and erosive processes in afflicted joints of people suffering from RA. The platform represents the life cycle of inflammatory cells, endothelium, synovial fibroblasts, and chondrocytes, as well as their products and interactions. The interplay between these processes culminates in clinically relevant measures for inflammation and erosion. The simulation model is deterministic, which allows tracing back the mechanism of action for a particular simulation result. Different patient phenotypes are represented by different virtual patients. The RA PhysioLab platform has been used to systematically and quantitatively study the predicted therapeutic effect of modulating several molecular targets, which resulted in a ranking of putative drug targets and a workflow to confirm the simulations experimentally. In addition, critical pathways were identified that drive the predicted disease outcome. Within these pathways, targets were identified from public literature that were not previously associated with arthritis. The model provides insights into the biology of RA and can be used as a platform for hypothesis-driven research. Case studies of therapies directed against IL-12 and IL-15 illustrate the approach, with emphasis on the analysis of system dynamics.

CYP1 determines the expression of several genes whose transcription is heme-dependent in yeast. It exerts regulatory functions even in the absence of heme, usually considered to be its effector. It mediates both positive and negative effects, depending on the target gene and on the redox state of the cell. In the presence of heme, it binds through a cysteine-rich domain in which a histidine residue occupies the position of the sixth and essential cysteine of the otherwise classical zinc cluster DNA-binding domain exemplified by GAL4. We constructed specific missense mutations in the potential CYP1 zinc cluster domain by site-directed mutagenesis and looked for regulatory effects of the mutated proteins under specific physiological conditions. We show that CYP1 does belong to the zinc cluster regulatory family since a sixth essential cysteine residue is indeed present, albeit at a modified position when compared to the consensus sequence. We also show that the amino acid preceding the first cysteine residue of the DNA-binding domain critically affects the efficiency of regulation both in the presence and in the absence of heme: mutations known to affect DNA binding under heme-sufficient conditions also affect regulation under heme-deficient conditions. We therefore surmise that regulation under heme-deficient conditions is dependent upon DNA binding.

In the accompanying paper, we present and analyse the sequence of a "superactivator" mutant allele of the CYP1 (HAP1) gene. This locus encodes a trans-acting pleiotropic positive regulator of the transcription of both isocytochrome c structural genes. In this paper, we present the genetic localization of the mutation and the sequence of the wild-type fragment that includes the mutation. The mutated phenotype that commutes the expression of the two isocytochrome structural genes (superactivation of CYP3 and inhibition of CYC1) results from a transversion in an AGT codon (serine) in the wild-type to an AGG codon (arginine) in the mutant. Moreover, we show that the missense mutation that affects the amino acid preceding the first cysteine of the "Zn finger" is responsible on its own account for the entire mutated phenotype. In all seven yeast regulatory proteins analysed so far, this position is occupied by a neutral amino acid (serine, alanine or glycine), thus the serine-arginine replacement is a radical one. This result is consistent with the hypothesis of alternative and mutually exclusive Zn fingers, formed either at low or high redox potential, recognizing the target sequences identified in the upstream regions of the CYC1 and CYP3 isocytochrome c structural genes.