Marked QTc Prolongation and Torsades de pointes in Patients with Chronic Inflammatory Arthritis

Mounting evidence indicates that in chronic inflammatory arthritis (CIA), QTc prolongation is frequent and correlates with systemic inflammatory activation. Notably, basic studies demonstrated that inflammatory cytokines induce profound changes in potassium and calcium channels resulting in a prolonging effect on cardiomyocyte action potential duration, thus on the QT interval on the electrocardiogram. Moreover, it has been demonstrated that in rheumatoid arthritis (RA) patients, the risk of sudden cardiac death is significantly increased when compared to non-RA subjects. Conversely, to date no data are available about torsades de pointes (TdP) prevalence in CIA, and the few cases reported considered CIA only an incidental concomitant disease, not contributing factor to TdP development. We report three patients with active CIA developing marked QTc prolongation, in two cases complicated with TdP degenerating to cardiac arrest. In these patients, a blood sample was obtained within 24 h from TdP/marked QTc prolongation occurrence, and levels of IL-6, TNFα, and IL-1 were evaluated. In all three cases, IL-6 was markedly elevated, ~10 to 100 times more than reference values. Moreover, one patient also showed high circulating levels of TNFα and IL-1. In conclusion, active CIA may represent a currently overlooked QT-prolonging risk factor, potentially contributing in the presence of other "classical" risk factors to TdP occurrence. In particular, a relevant role may be played by elevated circulating IL-6 levels via direct electrophysiological effects on the heart. This fact should be carefully kept in mind, particularly when recognizable risk factors are already present and/or the addition of QT-prolonging drugs is required

Circulating levels of adiponectin, resistin, and visfatin after mud-bath therapy in patients with bilateral knee osteoarthritis

6nononeAdipocytokines, including adiponectin, resistin, and visfatin may play an important role in the pathophysiology of osteoarthritis (OA). Spa therapy is one of the most commonly used non-pharmacological approaches for OA, but its mechanisms of action are not completely known. The aim of the present study was to assess whether a cycle of mud-bath therapy (MBT) influences the serum levels of adiponectin, resistin, and visfatin in patients with knee OA. As part of a prospective randomized, single blind-controlled trial evaluating the efficacy of MBT in knee OA, we included in this study 95 outpatients. One group (n = 49) received a cycle of MBT at the spa center of Chianciano Terme (Italy) in addition to the usual treatment, and one group (control group; n = 46) continued their regular care routine alone. Patients were assessed at basal time and at the end of the study (15 days) for clinical and biochemical parameters. Clinical assessments included spontaneous pain on a visual analog scale (VAS) score and the Western Ontario and McMaster Universities index (WOMAC) subscores for knee OA evaluated as total pain score (W-TPS), total stiffness score (W-TSS), and total physical function score (W-TPFS). Adiponectin, resistin and visfatin serum levels were assessed by enzyme immunoassay methods. At the end of the mud-bath therapy, serum adiponectin levels showed a significant decrease (p < 0.001), while no significant modifications were found in the control group at day 15. Serum resistin showed a significant decrease (p < 0.0001) in the MBT group at the end of the study and a significant increase in the control patients (p < 0.001). No significant modifications of visfatin were found in MBT. Furthermore, we tested the relationships between demographic and clinical parameters and adipocytokine concentrations measured in the MBT group at basal and at the end of the study. In conclusion, the present study shows that a cycle of MBT can modify serum levels of adiponectin and resistin but not the circulating levels of visfatin. In view of the recent evidences about the involvement of adiponectin and resistin in the pathogenesis and progression of OA, the decrease of these adipokines after mud-bath therapy may play a protective role in the course of the disease. However, it remains to be clarified which of the mechanisms of action of MBT may have determined the changes in serum levels of adiponectin and resistin that we observed.noneFioravanti, Antonella; Giannitti, Chiara; Cheleschi, Sara; Simpatico, Antonella; Pascarelli, Nicola Antonio; Galeazzi, MauroFioravanti, Antonella; Giannitti, Chiara; Cheleschi, Sara; Simpatico, Antonella; Pascarelli, NICOLA ANTONIO; Galeazzi, Maur

Low serum level of COMP, a cartilage turnover marker, predicts rapid and high ACR70 response to adalimumab therapy in rheumatoid arthritis.

The aim of this study was to evaluate serum biomarkers, used in clinical routine, to predict the American College of Rheumatology (ACR) response to long-term anti-TNF alpha treatment (adalimumab). Sera from 29 consecutive rheumatoid arthritis patients were analysed for anti-cyclic citrullinated peptide (anti-CCP), cartilage oligomeric matrix protein (COMP) and IgM and IgA RFs (class-specific rheumatoid factors) at the start of treatment with adalimumab and after 3, 6 and 12 months. The response to the therapy was evaluated by ACR 20, 50, 70 and by DAS 28 scores. The mean serum COMP level of the population did not change after treatment. However, patients with low serum COMP levels (50%) within 3 months, and also at 6 months, than patients with higher COMP values (ACR70<20%). This was also reflected by significantly higher decrease in DAS score at 3 (p<0.02) and 6 months (p<0.01) treatments. The IgM RF titre decreased significantly (p=0.02) after the therapy, but the percentage of serum positivity for anti-CCP and IgA/IgM RF did not change. No significant correlation was shown between serum COMP levels and C-reactive protein/erythrocyte sedimentation rate during the follow-up. Neither were any correlations shown between ACR/DAS 28 scores and anti-CCP, Ig M/IgA RFs. Our data indicate that low (<10 U/l) serum COMP before starting anti-TNF alpha treatment predicts a rapid (within 3 months) and high ACR70 response compared to RA patients with higher COMP values. This might reflect different mechanisms in the cartilage process in the RA disease at that time of treatment with different therapeutic sensitivity to anti-TNF alpha treatment

Comparison of different methods for the detection ofanti-Ro/SSA antibodies in connective tissue diseases.

OBJECTIVE: To compare the performance characteristics of various tests commonly used to detect anti-SSA/Ro autoantibodies in the sera of patients affected by connective tissue diseases (CTD). METHODS: Indirect immunofluorescence (IIF) with HEp-2000 as substrate (ImmunoConcepts, USA), Ouchterlony's double immunodiffusion (ID) (home made), commercial Varelisa ReCombi anti-Ro kit (Pharmacia & Upjohn, Germany), research kits (60 kDa and 52 kDa) with human recombinant antigens (Pharmacia & Upjohn, Germany) and a commercial western blot (WB) kit (MarDx, USA) were evaluated in our study. Sixty-four sera from patients affected by CTD were tested: 15 had primary Sjögren's syndrome (SS), 34 only had sicca syndrome, and 15 had systemic lupus erythematosus (SLE). Thirty sera from healthy subjects were selected as controls. RESULTS: 54 sera were positive by at least one method. The specificity of all tests was good. The prevalence of anti-SSA antibodies on 54 positive sera was 76% (ID), 89% (IIF), 89% (Varelisa), 89% (ELISA Ro-60 kDa), 67% (ELISA Ro-52 kDa) and 85% (WB). Some differences were found between WB and ELISA in the detection of anti-60 kDa SSA and anti-52 kDa SSA; in 3 SS sera only anti-52 kDa protein was found by WB. CONCLUSION: Our data confirm that, although IIF HEp 2000 (Immuno Concepts) and Varelisa anti-Ro (Pharmacia & Upjohn) both performed well, a combination of 2 or more methods must still be recommended for anti-SSA antibody detection

Prevalence of anti-Histone antibodies, their clinical significante and correlation with other autoantibodies in a color of italian scleroderma patients

PURPOSE: The aim of our study was to determine the prevalence, clinical significance of antibodies to individual histone components and to evaluate their correlation with other autoantibody specificities in a cohort of Italian SSc patients. Some authors, demonstrated high prevalence of anti-histone antibodies in Italian SSc patients, associated with cardiac and renal involvement, suggesting a prognostic value of these autoantibodies; however, these data need to be confirmed. METHODS: Serum from 112 adult SSc patients, classified as diffuse (dc) and limited cutaneous (lc) SSc subsets were analyzed for autoantibodies by indirect immunofluorescence, fluoroenzyme immunoassay and enzyme immunoassay. RESULTS: AHA were found in 13 patients (11.6%), nine with lcSSc and four with dcSSc. Among them, five patients were anti-Scl70+ and four were anti-CENP B+. The presence of AHA was not associated with multi-organ involvement or with diffuse subset, as already described. Anti-Scl70 was detected in 43% of patients, anti-CENP B in 32% and anti-RNA polymerase III in 7.1%. We confirmed the association between anti-Scl70 antibodies and pulmonary fibrosis (OR 15.75, p < 0.0001). CONCLUSION: In our experience, the very low prevalence of AHA in Italian SSc patients and the lack of association with clinical manifestations suggest that this test is of little clinical use; however, it would be worthwhile extending the study to a larger population of patients

Neutrophil extracellular traps release in gout and pseudogout depends on the number of crystals regardless of leukocyte count

Objectives: Microcrystal-induced arthritis is still an unresolved paradigm for medicine. Overt inflammation may be absent even when crystals occur in synovial fluid. Recently, the production of neutrophil extracellular traps (NETs) embedding monosodium urate crystals (MSU) has been proposed as a possible mechanism of the auto-resolution of the inflammatory phase during gout. We aimed to verify and quantify the release of NETs in synovial fluids during gout and pseudogout attacks and to compare any differences with respect to crystals and neutrophils number, and to analyze activation of necroptosis pathway in synovial fluid from crystal-induced arthritis. Methods: Synovial fluid samples were obtained by arthrocentesis from 22 patients presenting acute crystal-induced arthritis, gout or pseudogout (n = 11 each group), and from 10 patients with acute non-crystal arthritis as controls. NETosis was quantified in synovial fluid by nucleic acid stain and by quantification of human neutrophil elastase. Activation of p-MLKL was assessed by western blot. Results: We observed that synovial fluid neutrophils encountering MSU and CPPD crystals during episodes of gout and pseudogout release NETs in relation to the number of crystals in synovial fluid and irrespective of neutrophil density and type of crystal. This release was accompanied by necroptosis through the activation of the MLKL pathway. Conclusions: Our findings suggest that a role of NETs in crystal-induced arthritis is to "trap extracellular particles", including microcrystals. Embedding crystals in aggregates of NETs may be the basis of tophi and CPPD deposition and may have implications for disease evolution, rather than for spontaneous resolution of the acute attack

Serum immunoglobulin D levels in patients with Behçet's disease according to different clinical manifestations

OBJECTIVES: Behçet's disease (BD) is an autoinflammatory disorders mainly characterised by recurrent oral aphthosis, genital ulcers, and uveitis. The involvement of immunoglobulin D (IgD) in BD physiopathology is still unclear. The aim of our study was to assess the role of IgD in BD by comparing circulating levels of IgD in a cohort of BD patients and healthy controls (HC), as well as by correlating IgD levels with BD activity and different clinical presentations. METHODS: Serum IgD and SAA levels were analysed by ELISA assay in ninety-nine serum samples collected from 72 BD patients and in 29 HC subjects. RESULTS: Serum concentration of IgD were higher in BD patients compared with HC (p=0.029), in patients with high serum amyloid A (SAA) levels compared with patients with normal SAA levels (p=0.035), and among subjects with active mucocutaneous involvement compared with other patients (p=0.036). No correlations were identified between IgD serum levels and disease activity assessed by the BD current activity form (BDCAF) (p=0.640). No differences were observed in the IgD serum levels between patients with and without specific disease manifestations. Increased SAA levels (Odds Ratio = 3.978, CI: 1.356 -11.676) and active mucocutaneous BD manifestations (Odds Ratio = 4.286, CI: 1.192 - 15.407) were associated with a high risk for increased IgD serum levels. CONCLUSIONS: Serum IgD levels are significantly increased in BD patients, especially among patients with active mucocutaneous manifestations, suggesting a possible role of IgD in BD pathogenesis and in the onset of mucosal and skin lesions

Correlation of Serum Amyloid-A Levels, Clinical Manifestations, Treatment, and Disease Activity in Patients with Behçet's Disease

Background: Behçet’s disease (BD) is an inflammatory disorder potentially leading to life-and sight-threatening complications. No laboratory marker associated with disease activity or predicting the occurrence of disease manifestations is currently available. Objectives: To determine an association between serum amyloid-A (SAA) levels and disease activity via the BD Current Activity Form (BDCAF), to evaluate disease activity in relation to different SAA thresholds, to examine the association between single organ involvement and the overall major organ involvement with different SAA thresholds, and to assess the influence of biologic therapy on SAA levels. Methods: We collected 95 serum samples from 64 BD patients. Related demographic, clinical, and therapeutic data were retrospectively gathered. Results: No association was identified between SAA levels and BD disease activity (Spearman’s rho = 0.085, P = 0.411). A significant difference was found in the mean BDCAF score between patients presenting with SAA levels 200 mg/L (P = 0.027). SAA levels > 200 mg/L were associated with major organ involvement (P = 0.008). A significant association was found between SAA levels > 150 mg/dl and ocular (P = 0.008), skin (P = 0.002), and mucosal (P = 0.012) manifestations. Patients undergoing biologic therapies displayed more frequently SAA levels < 200 mg/L vs. patients who were not undergoing biologic therapies (P = 0.012). Conclusions: Although SAA level does not represent a biomarker for disease activity, it might be a predictor of major organ involvement and ocular disease relapse at certain thresholds in patients with BD. © 2018, Israel Medical Association. All rights reserved

Anti-cofactor autoantibodies in systemic lupus erythematosus: Prevalence, clinical and HLA class II associations

The aim of our study was to evaluate the clinical and HLA-class II allele associations of some anti-cofactor antibodies in a homogeneous group of European patients with SLE. One hundred thirty-six patients with SLE, fulfilling four or more of the ACR 1997 revised criteria for the classification of the disease, coming from 7 European countries, were enrolled consecutively. Anti-prothrombin (anti-PT), anti-annexin V (anti-AnnV), anti-protein C (anti-Cprot) and anti-protein S (anti-Sprot) were determined by using commercial ELISA kits. Molecular typing of HLA-DRB1, DRB3, DRB4, DRB5, DQA1, DQB1 and DPB1 loci was performed by using PCR-SSOP method, carried out using digoxygenin (DIG) labeled probes. The prevalence of anti-AnnV, anti-PT, anti-Cprot and anti-Sprot was 19%, 10.4%, 4.4% and 8.1%, respectively. Twenty-seven % of anti-AnnV positive patients reported migraine vs 5.5% of anti-AnnV negatives (p = 0.003, but p not significant, odds ratio (OR) = 6.4, 95% confidence interval (CI) = 2-21). Anti-PT, anti-AnnV and anti-Sprot were positively associated with some HLA alleles, but pc was not significant. In this study we have shown that some HLA alleles carry the risk to produce antibodies against phospholipid-binding proteins, but these association need confirmation in other studies, because they have never been reported and appear to be weak associations