Activated matrix metalloproteinase 8 in serum predicts severity of acute pancreatitis

Objectives: Severe acute pancreatitis (SAP) has high morbidity and mortality but there are no widely accepted predictive biomarkers in clinical use. Matrix metalloproteinases (MMPs) are active in tissue destruction and inflammatory responses. We studied whether serum levels of activated MMP-8 (aMMP8), MMP-9 and their regulators tissue inhibitor of matrix metalloproteinases (TIMP)-1, myeloperoxidase (MPO) and human neutrophil elastase (HNE) could predict the development of SAP. Methods: The study comprised 214 AP patients (revised Atlanta classification: 142 mild, MAP; 54 moderately severe, MSAP; 18 SAP) referred to Helsinki University Hospital. A venous blood sample was taken within 72 h from the onset of symptoms. Serum levels of aMMP-8 were determined using immunofluorometric assay, and those of MMP-9, TIMP-1, MPO and HNE using enzyme-linked immunosorbent assay. AP groups were compared using Jonckheere-Terpstra test and predictive value for SAP was analyzed using receiver operating characteristics (ROC) analysis. Results: Serum aMMP-8 levels were higher in SAP (median 657 ng/ml, interquartile range 542-738 ng/ ml) compared to MSAP (358 ng/ml, 175-564 ng/ml; p < 0.001) and MAP (231 ng/ml, 128-507 ng/ml; p < 0.001). Similar trend was seen with TIMP-1 and MPO. In ROC analysis aMMP-8, MPO and TIMP-1 emerged as potential markers for the development of SAP (areas under ROC curves 0.83, 0.71 and 0.69, respectively). Conclusions: Serum aMMP-8 measured early in the course of AP (within 72 h of symptom onset) predicted the development of SAP. (c) 2021 The Authors. Published by Elsevier B.V. on behalf of IAP and EPC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Peer reviewe

Baseline JAK phosphorylation profile of peripheral blood leukocytes, studied by whole blood phosphospecific flow cytometry, is associated with 1-year treatment response in early rheumatoid arthritis

Background: We found recently that baseline signal transducer and activator of transcription 3 phosphorylation in peripheral blood CD4(+) T cells of patients with early rheumatoid arthritis (RA) is associated with treatment response to synthetic disease-modifying antirheumatic drugs (DMARDs). This prompted us to study the baseline phosphorylation profiles of Janus kinases (JAKs) in blood leukocytes with respect to treatment response in early RA. Methods: Thirty-five DMARD-naive patients with early RA provided blood samples for whole blood flow cytometric determination of phosphorylation of JAKs in CD4(+) and CD8(+) T cells, CD19(+) B cells, and CD14(+) monocytes. Treatment response was determined after 1 year of treatment with synthetic DMARDs, with remission defined as absence of tender and swollen joints and normal erythrocyte sedimentation rate. Exact logistic regression was used to investigate the association of baseline variables with treatment response. Ninety-five percent CIs of means were estimated by bias-corrected bootstrapping. Results: High JAK3 phosphorylation in CD4(+) and CD8(+) T cells, CD19(+) B cells, and CD14(+) monocytes and low JAK2 phosphorylation in CD14(+) monocytes were significantly associated with remission following treatment with synthetic DMARDs. Conclusions: Baseline JAK phosphorylation profile in peripheral blood leukocytes may provide a means to predict treatment response achieved by synthetic DMARDs among patients with early RA.Peer reviewe

Multiparameter Phospho-Flow Analysis of Lymphocytes in Early Rheumatoid Arthritis: Implications for Diagnosis and Monitoring Drug Therapy

The precise mechanisms involved in the initiation and progression of rheumatoid arthritis (RA) are not known. Early stages of RA often have non-specific symptoms, delaying diagnosis and therapy. Additionally, there are currently no established means to predict clinical responsiveness to therapy. Immune cell activation is a critical component therefore we examined the cellular activation of peripheral blood mononuclear cells (PBMCs) in the early stages of RA, in order to develop a novel diagnostic modality.PBMCs were isolated from individuals diagnosed with early RA (ERA) (n = 38), longstanding RA (n = 10), osteoarthritis (OA) (n = 19) and from healthy individuals (n = 10). PBMCs were examined for activation of 15 signaling effectors, using phosphorylation status as a measure of activation in immunophenotyped cells, by flow cytometry (phospho-flow). CD3+CD4+, CD3+CD8+ and CD20+ cells isolated from patients with ERA, RA and OA exhibited activation of multiple phospho-epitopes. ERA patient PBMCs showed a bias towards phosphorylation-activation in the CD4+ and CD20+ compartments compared to OA PBMCs, where phospho-activation was primarily observed in CD8+ cells. The ratio of phospho (p)-AKT/p-p38 was significantly elevated in patients with ERA and may have diagnostic potential. The mean fluorescent intensity (MFI) levels for p-AKT and p-H3 in CD4+, CD8+ and CD20+ T cells correlated directly with physician global assessment scores (MDGA) and DAS (disease activity score). Stratification by medications revealed that patients receiving leflunomide, systemic steroids or anti-TNF therapy had significant reductions in phospho-specific activation compared with patients not receiving these therapies. Correlative trends between medication-associated reductions in the levels of phosphorylation of specific signaling effectors and lower disease activity were observed.Phospho-flow analysis identified phosphorylation-activation of specific signaling effectors in the PB from patients with ERA. Notably, phosphorylation of these signaling effectors did not distinguish ERA from late RA, suggesting that the activation status of discrete cell populations is already established early in disease. However, when the ratio of MFI values for p-AKT and p-p38 is >1.5, there is a high likelihood of having a diagnosis of RA. Our results suggest that longitudinal sampling of patients undergoing therapy may result in phospho-signatures that are predictive of drug responsiveness

Induction of remission in female rheumatoid arthritis patients is associated with stabilization of myocardial abnormalities: a prospective cardiac magnetic resonance follow-up study

Julkaisua ei hallinnoi Genomibiologian yksikkö, mutta en saanut yksikköä vaihdettua. Päätekijöiden affiliaatio: Department of Rheumatology, University of Helsinki and Helsinki University Hospital , Helsinki, Finland. Oma julkaisuun liittyvä affiliaationi: University of Helsinki, Faculty of Medicine, Clinicum.Objectives: To study whether female patients with active rheumatoid arthritis (RA) have myocardial abnormalities and whether progression of myocardial involvement can be attenuated by disease-modifying anti-rheumatic drugs (DMARDs). Method: Cardiac magnetic resonance (cMR; 1.5 or 3.0 T), including late gadolinium enhancement (LGE), T1 relaxation time, and ventricular functions, was performed in 30 patients with untreated active early RA starting first DMARDs, and 28 patients with chronic RA with inadequate response to conventional synthetic DMARDs starting biological DMARDs. cMR was repeated in RA patients 1 year later. cMR was conducted once in 22 fibromyalgia (FM) subjects and in 35 healthy volunteers serving as controls. All subjects were non-smoking females without coronary heart disease, heart failure, or diabetes. Results: Compared with controls, 58 RA patients had slightly lower ventricular function, although in the normal range, and longer T1 time at baseline. None of the FM subjects had LGE, but it was frequent in RA (67%). During the 1 year DMARD treatment, Disease Activity Score based on 28-joint count-C-reactive protein declined, ventricular functions tended to improve, but the number of patients with LGE remained unchanged. However, the number of LGE-positive heart segments either decreased or stayed the same in 91% of RA patients. In early RA patients, achieving tight remission was associated with LGE stabilization, after adjustment for age, metabolic syndrome, baseline inflammatory activity, and leisure-time physical activity. Conclusion: Treatment targeted to tight remission in early stages of RA seems to be important to prevent not only joint damage but also myocardial abnormalities.Peer reviewe

Circulating Cytokine Levels and Cardiovascular Disease Risk Profile in Young Adult Offspring of Women with Type 1 Diabetes

Introduction: Cytokines are key players in the development of both type 1 diabetes (T1D) and cardiovascular disease (CVD). Offspring of women with T1D are known to have an increased risk of early-onset CVD. We studied whether an increased risk of CVD can be observed in the cytokine profile among young adult offspring of women with T1D.Methods: This cross-sectional case-control study included 67 offspring of women with T1D (cases) and 79 control participants (controls). At an age of 18-23 years, they participated in a clinical assessment including laboratory tests and questionnaires. Cytokine levels were analyzed from venous blood samples after 10 h fasting using Quansys biosciences Q-Plex (TM) High Sensitivity Human Cytokine Array.Results: Circulating cytokine levels were in general similar between the groups. The circulating levels of interferon-gamma (1.78 [IQR 1.20, 2.36] pg/mL versus 2.57 [IQR 1.50, 3.89] pg/mL) (p = 0.006) were lower in cases than controls.Conclusion: The findings did not support our hypothesis that serum cytokine profile, determined in early adulthood, was associated with a more adverse CVD risk profile in offspring of women with T1D. Further studies are warranted to find out whether cytokines could serve as early biomarkers of CVD development or whether changes in the cytokine levels over years could be used to monitor CVD progression in offspring of women with T1D.Peer reviewe

Circulating soluble E-selectin in early rheumatoid arthritis: a prospective five year study

Background: Soluble E-selectin (sE-selectin) is a marker of activation of vascular endothelium. Objective: To examine serum levels of sE-selectin in a cohort of 85 patients with early rheumatoid arthritis (RA) followed up for five years. Methods: sE-selectin levels were assessed annually using an enzyme linked immunosorbent assay (ELISA) and related to simultaneously obtained clinical and laboratory measures. Joint inflammation was evaluated by active joint count, functional status by Health Assessment Questionnaire (HAQ), and radiographic findings in hands and feet by the Larsen method. Laboratory tests included serum C reactive protein (CRP) level, erythrocyte sedimentation rate, blood haemoglobin level, white blood cell count (WBC), and platelet count. Area under the curve (AUC) was calculated for each variable, and Jonckheere's test for ordered alternatives was applied to assess significance of association between sE-selectin AUC tertiles and other variables. Baseline sE-selectin tertiles were related to change in Larsen score and HAQ score at five years. Odds ratios (OR) with 95% confidence interval (CI) were calculated using univariate and multivariate logistic regression. Results: sE-selectin levels were associated with CRP level (p=0.012), WBC (p=0.037), active joint count (p=0.019), progression of joint destruction (p=0.038), and HAQ score at five years (p=0.021), but not with extra-articular symptoms or comorbidity. Baseline sE-selectin levels in the third tertile predicted the HAQ score at five years (OR 4.18, 95% CI 1.15 to 15.22). sE-selectin levels of patients did not differ significantly from those of healthy control subjects. Conclusion: The degree of activation of vascular endothelium is associated with activity and outcome of early RA

Interleukin 8 and hepatocyte growth factor in predicting development of severe acute pancreatitis

<p><i>Objectives</i>: We aimed to study if interleukin (IL) 8 and hepatocyte growth factor (HGF) predict development of severe acute pancreatitis (SAP) among patients without organ dysfunction (OD) at presentation, and if they discriminate transient OD from persistent OD among patients presenting with OD. <i>Methods</i>: From prospectively collected cohort of 176 AP patients and 32 healthy controls, plasma levels of IL-8 and HGF were determined within 5 days after symptom onset using an enzyme-linked immunosorbent assay. <i>Results</i>: AP was severe in 23 patients, of whom 10 did not have clinical signs of OD at presentation. IL-8 and HGF levels increased along with the severity of AP (<i>P</i> < 0.001). In patients without OD at study entry, IL-8 and HGF values predicted the development of SAP with the AUCs of 0.73 (95% CI, 0.56–0.91) and 0.79 (95% CI, 0.66–0.93), respectively. Of all patients, 22 presented with OD, and among them IL-8 predicted persistence of OD with the AUC of 0.88 (95% CI 0.69–1.0). Combining IL-8 and HGF did not improve the models. <i>Conclusions</i>: In AP patients without OD at presentation, circulating levels of IL-8, or HGF, may predict the development of SAP. In patients presenting with OD, IL-8 level may discriminate the patients with transient OD from those with persistent OD.</p