Selective involvement of ERK and JNK mitogen-activated protein kinases in early rheumatoid arthritis (1987 ACR criteria compared to 2010 ACR/EULAR criteria): a prospective study aimed at identification of diagnostic and prognostic biomarkers as well as therapeutic targets

Objectives To investigate the expression and activation of mitogen-activated protein kinases in patients with early arthritis who are disease-modifying antirheumatic drug (DMARD) naive. Methods A total of 50 patients with early arthritis who were DMARD naive (disease duration <1 year) were prospectively followed and diagnosed at baseline and after 2 years for undifferentiated arthritis (UA), rheumatoid arthritis (RA) (1987 American College of Rheumatology (ACR) and 2010 ACR/European League Against Rheumatism (EULAR) criteria), or spondyloarthritis (SpA). Synovial biopsies obtained at baseline were examined for expression and phosphorylation of p38, extracellular signal regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) by immunohistochemistry and digital analysis. Synovial tissue mRNA expression was measured by quantitative PCR (qPCR). Results ERK and JNK activation was enhanced at inclusion in patients meeting RA criteria compared to other diagnoses. JNK activation was enhanced in patients diagnosed as having UA at baseline who eventually fulfilled 1987 ACR RA criteria compared to those who remained UA, and in patients with RA fulfilling 2010 ACR/EULAR criteria at baseline. ERK and JNK activation was enhanced in patients with RA developing progressive joint destruction. JNK activation in UA predicted 1987 ACR RA classification criteria fulfilment (R-2=0.59, p=0.02) after follow-up, and disease progression in early arthritis (R-2=0.16, p <0.05). Enhanced JNK activation in patients with persistent disease was associated with altered synovial expression of extracellular matrix components and CD44. Conclusions JNK activation is elevated in RA before 1987 ACR RA classification criteria are met and predicts development of erosive disease in early arthritis, suggesting JNK may represent an attractive target in treating RA early in the disease proces

The Features of the Synovium in Early Rheumatoid Arthritis According to the 2010 ACR/EULAR Classification Criteria

OBJECTIVES: It has been shown in early arthritis cohorts that the 2010 ACR/EULAR criteria for rheumatoid arthritis (RA) enable an earlier diagnosis, perhaps at the cost of a somewhat more heterogeneous patient population. We describe the features of synovial inflammation in RA patients classified according to these new criteria. METHODS: At baseline, synovial tissue biopsy samples were obtained from disease-modifying antirheumatic drug (DMARD)-naïve early RA patients (clinical signs and symptoms <1 year). Synovial tissue was analyzed for cell infiltration, vascularity, and expression of adhesion molecules. Stained sections were evaluated by digital image analysis. Patients were classified according to the two different sets of classification criteria, autoantibody status, and outcome. FINDINGS: Synovial tissue of 69 RA patients according to 2010 ACR/EULAR criteria was analyzed: 56 patients who fulfilled the criteria for RA at baseline and 13 who were initially diagnosed as undifferentiated arthritis but fulfilled criteria for RA upon follow up. The synovium at baseline was infiltrated by plasma cells, macrophages, and T cells as well as other cells, and findings were comparable to those when patients were selected based on the 1987 ACR criteria for RA. There was no clear cut difference in the characteristics of the synovium between RA patients initially diagnosed as undifferentiated arthritis and those who already fulfilled classification criteria at baseline. CONCLUSION: The features of synovial inflammation are similar when the 2010 ACR/EULAR classification criteria are used compared to the 1987 ACR criteria

Synovial tissue expression of different cellular markers.

<p>Synovial tissue expression of, CD55+ fibroblast-like synoviocytes (FLS), CD3+ T CD68+ macrophages, CD3+ T cells, CD22+ B cells, CD138+ plasma cells. A:RA patient according to the 1987 ACR criteria, B:RA patient according to the 2010 ACR/EULAR criteria.</p

Baseline patient characteristics.

<p>Data are presented as median (interquartile range) or number (n [%]), as appropriate. Baseline characteristics were compared between the two diagnostic groups using a Mann-Whitney U test or a Chi2-test (sex, RF pos, ACPA pos). A <i>P</i>-value of <0.05 was considered statistically significant (bold). RA = rheumatoid arthritis; RA (all) = all patients with RA diagnosis after 2 years of follow up; RA−RA = RA at baseline and follow up; UA−RA = initially UA, but definitive diagnosis of RA at follow up; dis.dur. = disease duration; VAS = visual analog scale; MS = morning stiffness; ESR = erythrocyte sedimentation rate; CRP = C-reactive protein; TJC68 = tender joint count; SJC66 = swollen joint count; RF = IgM rheumatoid factor; ACPA = anti-citrullinated protein antibodies; pos = serum positive.</p

Expression of synovial phenotypic and vascular markers in patients who fulfilled 2010 ACR/EULAR criteria for RA at baseline after follow up and in the patients who fulfilled1987 ACR criteria.

<p>Values are presented as median (interquartile range). A Mann-Whitney U test was used to compare the different diagnostic groups; a <i>P</i>-value of <0.05 was considered statistically significant. RA = rheumatoid arthritis. CD3 refers to T cells; CD55– fibroblast-like synoviocytes; CD68– macrophages; CD22– B cells; CD138– plasma cells; tryptase – mast cells. L = intimal lining layer; SL = synovial sublining; vWF = von Willebrand factor; VEGF = vascular endothelial growth factor; VCAM-1 = vascular cell adhesion molecule-1. IOD = integrated optical density.</p

Expression of phenotypic and vascular markers in synovial tissue of RA patients with self-limiting, persistent non-erosive or persistent erosive disease.

<p>Values are presented as median (interquartile range). A Kruskal-Wallis test was used to compare the different diagnostic groups; a <i>P</i>-value of <0.05 was considered statistically significant (bold). CD3 refers to T cells; CD55– fibroblast-like synoviocytes; CD68– macrophages; CD22– B cells; CD138– plasma cells; tryptase – mast cells. L = lining; SL = sublining; vWF = von Willebrand factor; VEGF = vascular endothelial growth factor; VCAM-1 = vascular cell adhesion molecule-1. IOD = integrated optical density.</p

Patient classification.

<p>Patient classification at baseline and after 2 years follow up according to 2010 ACR/EULAR criteria, and according to outcome after 2 years follow up.</p

Validation of a new Aspergillus real-time PCR assay for direct detection of Aspergillus and azole resistance of Aspergillus fumigatus on bronchoalveolar lavage fluid

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