New pro-inflammatory cytokine IL-40 is produced by activated neutrophils and plays a role in the early stages of seropositive rheumatoid arthritis.

OBJECTIVE: Interleukin (IL)-40 is a new cytokine related to immune system function and malignancies. Recently, an association of IL-40 with rheumatoid arthritis (RA) and externalisation of neutrophil extracellular traps (NETosis) was found. As neutrophils are implicated in RA development, we investigated IL-40 in early stages of RA (ERA). METHODS: IL-40 was determined in serum of treatment naïve patients with ERA at baseline (n=60) and 3 months after initiation of conventional therapy and in healthy controls (HC; n=60). Levels of IL-40, cytokines and NETosis markers were measured by ELISA. NETosis was visualised by immunofluorescence. In vitro experiments were performed on peripheral blood neutrophils from ERA patients (n=14). Cell-free DNA was analysed in serum and supernatants. RESULTS: Serum IL-40 was elevated in ERA compared with HC (p<0.0001) and normalised after 3 months of therapy (p<0.0001). Baseline serum IL-40 correlated with rheumatoid factor (IgM) (p<0.01), anti-cyclic citrullinated peptide (p<0.01) autoantibodies and NETosis markers (proteinase 3; neutrophil elastase (NE); myeloperoxidase) (p<0.0001). Levels of NE significantly decreased after therapy (p<0.01) and correlated with the decrease of serum IL-40 (p<0.05). In vitro, neutrophils enhanced IL-40 secretion following NETosis induction (p<0.001) or after exposure to IL-1ß, IL-8 (p<0.05), tumour necrosis factor or lipopolysaccharide (p<0.01). Recombinant IL-40 up-regulated IL-1ß, IL-6 and IL-8 (p<0.05 for all) in vitro. CONCLUSION: We showed that IL-40 is significantly up-regulated in seropositive ERA and decreases after conventional therapy. Moreover, neutrophils are an important source of IL-40 in RA, and its release is potentiated by cytokines and NETosis. Thus, IL-40 may play a role in ERA.

Chemokine and Cytokine Profiles in Patients with Hand Osteoarthritis.

BACKGROUND: The development of hand osteoarthritis (HOA) and its progression into the erosive subset are unclear, but inflammation is suspected to be the main source. To verify the involvement of inflammation in HOA pathogenesis, we evaluate serum inflammatory mediators and their association with HOA-related clinical features in patients. METHODS: 153 participants (50 non-erosive HOA patients, 54 erosive HOA patients, and 49 healthy control subjects) were included in this study. All patients underwent clinical examination, which included assessment of tender and swollen small hand joints, ultrasound (US) examination, and self-reported measures (e.g., AUSCAN or algofunctional indexes). Serum inflammatory mediators were quantified using human cytokine 27-plex immunoassay. We employed linear modelling, correlation analysis, and resampling statistics to evaluate the association of these mediators to HOA. RESULTS: We identified increased levels of nine inflammatory mediators (e.g., eotaxin, monocyte chemoattractant protein 1, interleukin-8, and tumour necrosis factor) in HOA patients compared to healthy controls. Increased mediators correlated with ultrasound findings as well as with clinically tender and swollen joint counts in patients with erosive HOA. However, none of the mediators distinguished between erosive and non-erosive HOA subtypes. CONCLUSION: Our findings support the hypothesis on the involvement of inflammation in HOA.

Serum Calprotectin Discriminates Subclinical Disease Activity from Ultrasound-Defined Remission in Patients with Rheumatoid Arthritis in Clinical Remission.

OBJECTIVE: Clinical remission in some patients with rheumatoid arthritis (RA) may be associated with ongoing synovial inflammation that is not always detectable on clinical examination or reflected by laboratory tests but can be visualized by musculoskeletal ultrasound. The goal of our study was to determine the levels of serum calprotectin, a major leukocyte protein, in patients with RA in clinical remission and to investigate the ability of serum calprotectin levels to distinguish patients in ultrasound-defined remission from those with residual ultrasound subclinical inflammation. METHODS: Seventy RA patients in clinical remission underwent clinical and ultrasound examination. Ultrasound examination was performed according to the German US7 score. Ultrasound remission was defined as grey scale (GS) range 0-1 and power Doppler (PD) range 0. The levels of serum calprotectin and C-reactive protein (CRP) were determined. The discriminatory capacity of calprotectin and CRP in detecting residual ultrasound inflammation was assessed using ROC curves. RESULTS: The total number of patients fulfilling the DAS28-ESR, DAS28-CRP, SDAI and CDAI remission criteria was 58, 67, 32 and 31, respectively. Residual synovial inflammation was found in 58-67% of the patients who fulfilled at least one set of clinical remission criteria. Calprotectin levels were significantly higher in patients with residual synovial inflammation than in those with ultrasound-defined remission (mean 2.5±1.3 vs. 1.7±0.8 µg/mL, p<0.005). Using ultrasound-defined remission criteria, calprotectin had an AUC of 0.692, p<0.05 using DAS28-ESR remission criteria and an AUC of 0.712, p<0.005 using DAS28-CRP remission criteria. Calprotectin correctly distinguished ultrasound remission from subclinical activity in 70% of patients. CRP (AUC DAS28-ESR = 0.494, p = NS; AUC DAS28-CRP = 0.498, p = NS) had lower and insignificant discriminatory capacity. CONCLUSION: The present study demonstrates the potential of calprotectin to distinguish RA patients in both clinical and ultrasound-defined remission from patients in clinical remission but with residual subclinical disease activity.

High levels of metastasis-inducing S100A4 protein and treatment outcome in early rheumatoid arthritis: data from the PERAC cohort.

Abstract The aim of this study was to evaluate the role of S100A4 as a biomarker in patients with early rheumatoid arthritis (RA). S100A4 levels were measured in 59 patients with early RA and in 41 healthy controls. The association between the S100A4 levels and the treatment outcome after 12 months was determined using multivariate regression analysis. Serum S100A4 levels were significantly higher in the patients with early RA than in the healthy subjects and significantly decreased after 3 months of treatment. Diseases activity at 12 months was significantly higher in female patients who had initially high levels of S100A4. Persistently high S100A4 levels predicted poor treatment outcome and S100A4 may thus represent promising biomarker for assessing treatment response in patients with RA.

Dual-phase dual-energy CT in patients with lung cancer: assessment of the additional value of iodine quantification in lymph node therapy response.

OBJECTIVES: To investigate the potential contribution of iodine uptake calculation from dual-phase dual-energy CT (DE-CT) for lymph node staging and therapy response monitoring in lung cancer patients. METHODS: Retrospective analysis of 27 patients with non-small cell lung carcinoma (NSCLC), who underwent dual-phase DE-CT before and after chemotherapy, was performed. Iodine uptake (mg/mL) and total iodine uptake (mg) were calculated using prototype software in the early (arterial) and late (venous) post-contrast circulatory phase in 110 mediastinal lymph nodes. The arterial enhancement fraction (AEF) was calculated and compared with lymph node size and response to chemotherapy. RESULTS: A significant difference of AEF was observed between enlarged (90.4%; 32.3-238.5%) and non-enlarged (72.7%; -37.5-237.5%) lymph nodes (p = 0.044) before treatment onset. A significantly different change of AEF in responding (decrease of 26.3%; p = 0.022) and non-responding (increase of 43.0%; p = 0.031) lymph nodes was demonstrated. A higher value of AEF before treatment was observed in lymph nodes with subsequent favourable response (88.6% vs. 77.7%; p = 0.122), but this difference did not reach statistical significance. CONCLUSIONS: The dual-phase DE-CT examination with quantification of ratio of early and late post-contrast iodine uptake is a feasible and promising method for the functional evaluation of mediastinal lymph nodes including therapy response assessment. KEY POINTS: • Dual-phase DE-CT is beneficial for mediastinal lymph node assessment in NSCLC. • Arterial to venous iodine uptake ratio was higher in enlarged lymph nodes. • Change of arterial enhancement fraction correlated to therapy response.