flow cytometry, in relation to clinical parameters and previously established LN classes assessed according to the ISN/RPS 2003 classification. Results Lymphocytes percentages in class IV were different from classes III, V or a combination of III and V. In the latter classes, the percentages of the Tregs and Th17 cells were significantly lower, whereas in class IV the increase in FOXP3 in the Tregs and Th17 cells over six months period was significantly higher (Table 1). Changes in glomerular filtration rate and SLEDAI within 5 years did not correlate with single or repeated Tregs measurements. Conclusions Differences in lymphocyte proportions between class IV and other classes may suggest its distinct pathogenesis and warrants further investigations on their role as LN biomarker.
BackgroundRemission is achievable in many patients receiving biologic therapies. Only limited information on predictors of discontinuation of biologic therapy in patients with rheumatoid arthritis (RA) is available.ObjectivesTo evaluate how often biologic DMARDs are discontinued due to remission and to identify predictors of discontinuation of biologic treatment in patients from a Spanish registry.MethodsRetrospective, observational cohort study based on data from a national registry. RA patients receiving a first biologic DMARD for ≥3 consecutive months between April 1998 and December 2013 were included. Patients receiving rituximab were excluded. The study endpoint was defined as discontinuation of biologic DMARD due to remission, defined by treating physician. Censoring occurred administratively (end of registry data), when patients ceased treatment due to other causes (side effect, lack of efficacy, pregnancy, etc.) or due to loss to follow up. Multivariate proportional sub-distribution hazards (SHR) models were used to evaluate associations between predictor factors of discontinuation due to remission, discontinuation due to lack of efficacy, side effects, loss to follow-up or other causes as competing events.Results3,516 patients were included, of which 3,161 patients had received ≥3 months of biologic DMARD: 753 patients discontinued treatment due to side effects, 867 patients due to lack of efficacy, 101 were lost to follow-up, 143 for other reasons, 48 due to pregnancy, and 15 patients due to unknown reasons. 1175 patients were receiving biological DMARD at the study conclusion. Only 59 (1.8%) patients discontinued biologic therapy due to remission. The Table shows baseline characteristics of patients at initiation of biologic DMARDs by discontinuation for remission.No remission*Discontinuation due to remissionp valueN=3,102N=59Mean age (years ± SD)53.9±13.258.5±12.40.007Sex (female %)79.988.10.11Mean disease duration (years ± SD)9.3±8.77.0±6.00.04Seropositive RA (%)89.389.80.89Current smoking12.26.80.20Extra-articular disease (%)20.115.30.35Nodular disease (%)7.45.10.25Mean DAS-28 ± SD3.75±2.854.22±2.470.21Methotrexate (ever, %)56.762.70.35Steroids use (at index date, %)53.459.30.37DMARDs use (at index date, %)71.271.20.99Anti-TNF therapy (as first treatment, %)93.998.30.15*Included all patients censored and those still receiving biologic DMARDs.After multivariate SHR analysis, sex (female) (SHR 2.81, 95% CI 1.01-7.83), age at onset (SHR 1.04, 95% CI 1.01-1.07) and disease duration (HR 0.94, 95% CI 0.90-0.98) were significant predictors of discontinuation due to remission adjusting by methotrexate and steroids use.ConclusionsLess than 2% of RA patients discontinued biologic DMARD therapy due to disease remission. Sex, age at onset and disease duration were predictors of this discontinuation. The prognosis of biologic-free patients after remission is still unknown and further studies are required to determine their clinical outcomes.Disclosure of InterestNone declared
BackgroundTNF-like WEAK inducer of apoptosis (TWEAK) is able to increase the expression of various molecules involved in the inflammatory response with relevant effects also in angiogenesis. The pathological functions of TWEAK are primarily attributed to its ability to induce the expression of several pro-inflammatory cytokines, chemokines and cell adhesion molecules, including vascular cell adhesion molecule-1 (VCAM-1) (1). Some previous studies (most of them in Caucasic, Afro-American and Asiatic cohorts) have demonstrated clinical utility of VCAM-1 and TWEAK as biomarkers in patients with systemic lupus erythematosus SLE (2).ObjectivesTo evaluate the diagnostic value of urinary VCAM-1 and TWEAK in a cohort of Latin-American patients with SLE.MethodsPatients meeting the revised ACR criteria for SLE were recruited from 2 different centers at Medellín and Baranquilla, Colombia. Urinary levels of VCAM-1 (uVCAM-1) and TWEAK (uTWEAK) were measured using an ELISA kit (R&D system, USA). SLE activity was measured with SLEDAI. Inactive LN was defined by the presence of: 24 hours proteinuria ≤500 mg/dl, inactive urine sediments and stable serum creatinine. Mann-Whitney tests were used to compare data and Spearman's rank correlations were used to examine associations.ResultsOne hundred and fifty eight SLE patients were recruited (89% female) with median age of 32.8±12.1 years and median disease duration of 7.27±6.6 years. Mestizo (77%) and African Latin-American patients (20%) were majority. Mean SLEDAI score was 8.5±8.7. One hundred and four patients (64%) had lupus nephritis (LN). 76 out of 104 patients had biopsy proven LN, in 62% of cases with proliferative forms. uVCAM-1 and uTWEAK were significantly higher in patients with LN than without LN. At the same time, uVCAM-1 and uTWEAK were significantly higher in patients with active vs inactive LN (Figure). uVCAM-1 (581±1197 vs 189±256 ng/ml, p<0.001) and uTWEAK levels (3202±3778 vs 1123±1873 pg/ml, p=0.038) were significantly higher in patients with Class V LN in comparison with other LN classes. uVCAM-1 and uTWEAK levels had a mild positive correlation with SLEDAI (r=0.22 and r=0.16, respectively). In addition, uTWEAK correlated with 24 hours proteinuria (r=0.28). No significant correlation was found between uVCAM-1 and uTWEAK.Figure 1.Urinary levels of VCAM-1 and TWEAK in patients with and without LN (A and B) and in patients with active vs inactive LN (C and D).ConclusionsuVCAM-1 and uTWEAK are useful biomarkers in Latin-American patients with SLE for the identification of patients with LN and active LN. In addition, urinary levels of VCAM-1 and TWEAK were significantly more elevated in patient with membranous LN.References González-Sánchez DA, Άlvarez CM, Vásquez G, Gόmez-Puerta JA. Role of TWEAK/Fn14 signalling pathway in lupus nephritis and other clinical settings. Nefrologia. 2016. pii: S0211–6995(16)30084–4.Skeoch S, Haque S, Pemberton P, Bruce IN. Cell adhesion molecules as potential biomarkers of nephritis, damage and accelerated atherosclerosis in patients wit...
BackgroundThere is an increasing interest in the study of domain reactivity of antibodies against β2 glycoprotein I (anti-B2GPI) in patients with antiphospholipid syndrome (APS). Antibodies targeting domain 1 of the molecule (anti-D1) as the most relevant autoantibody subpopulation. Previous information of anti-D1 B2GPI comes from APS cohorts with Caucasian, Asian, and African-American patients. However, there are no studies in Mestizo and Afro-Latin American patients.ObjectivesOur aim was to evaluate the prevalence of Anti-D1 B2GPI antibodies in a cohort of Colombian patients with systemic lupus erythematosus (SLE) with and without thrombosis, primary APS and patients with previous history of recurrent miscarriages (RM) without APS criteria.MethodsIn this cross-sectional study we measured Anti-D1 B2GPI antibodies in a group of patients from Rheumatology Department, Coagulation clinic and Recurrent Pregnancy Loss Program at the Reproduction Group at Hospital San Vicente Fundaciόn and Universidad de Antioquia, respectively, at Medellín, Colombia. Anti-D1 B2GP1 antibodies were tested using a chemiluminescent immunoassay (QUANTA Flash B2GPI IgG, Inova Diagnostics). Mann-Whitney tests were used to compare data.ResultsOne hundred and seventy seven (median age 33.5±12.1 years; 89% women) patients were included. One hundred thirty eight patients had SLE (78%), 27 primary APS (15%) and 13 RM (7%). Fifty five (31%) out of 177 patients had history of thrombosis and 41 (23%) of pregnancy losses. Overall, Anti-D1 B2GPI antibodies were positive (>20 CU) in 35 (20%) of patients. Anti-D1 B2GPI were positive in 23%, 17% and 0% of patients with primary APS, SLE and RM, respectively. Overall, serum Anti-D1 B2GPI were significantly higher in patients with than without previous thrombosis (149.1±336.1 vs 16.3±61.8 CU, p<0.0001) and in patients (SLE or primary APS) with previous history of pregnancy losses (40.2±123.1 vs 21.0±74.5 CU, p=0.04). Anti-D1 B2GPI were significantly higher in patients with primary APS vs SLE with thrombosis, and in patients with SLE with thrombosis vs SLE without thrombosis (Figure). No clinical associations were found among Anti-D1 B2GPI antibodies and other APS features.Figure 1.Mean serum levels of Anti-D1 B2GPI in a cohort of 177 patients.ConclusionsSerum titers of Anti-D1 B2GPI antibodies were more than 9 times and 2 times higher in patients with thrombosis and pregnancy losses, respectively. In addition, serum titers were significantly higher in patients with primary APS than in SLE patients with thrombosis. Whether Anti D1- B2GPI antibodies titers are useful to differentiate patient with primary and secondary APS requires further analysis.AcknowledgementsJA Gόmez-Puerta was supported by Colciencias (conv. 656 de 2014). Anti-D1 B2GPI antibodies were provided by Inova, Werfen, ColombiaDisclosure of InterestNone declared
BackgroundHigh mobility group box protein 1 (HMGB1) is a nuclear DNA-binding protein that can function as an alarmin when is released from activated and dying cells. In association with nucleosomes, HMGB1 may contribute to the pathogenesis of systemic lupus erythematosus (SLE). Some previous reports have associated HMGB1 with the pathogenesis of cutaneous lupus and lupus nephritis (LN). HMGB1 may also be contained in microparticles (MPs). These vesicles have a wide spectrum of biological activities in intercellular communication, and they compete with apoptotic cells to bind mononuclear phagocytes.ObjectivesTo evaluate the association of MP-HMGB1+ circulating with LN and to correlate them with LN activity.MethodsBlood samples from 60 SLE patients were used to isolated MPs from platelet-poor plasma by centrifugation and their count, cell source and phenotype were characterized by flow cytometry. Renal pathology was reported using the standardized International Society of Nephrology/Renal Pathological Society classification. Inactive lupus nephritis (LN) was defined by the presence of one or more of the following criteria: 24 hrs proteinuria 500 mg/dl or inactive urine sediments (<5 red cells/HPF) and no red cell casts and no leucocyturia (<5 white cells/HPF) and stable serum creatinine.ResultsMean age of SLE patients was 31.9±10.8 years, and mean disease duration was 7.8±6.2 years. 73% patients had LN and 89% were female. Patients with LN had significantly higher frequency of MP-HMGB1+, no significant differences were found among patients with active versus inactive LN or among patients with proliferative vs non-proliferative LN; MP-HMGB1+ had a moderate positive correlation with disease activity (SLEDAI, r=0.367, p=0.020), anti-C1q antibodies titers (r=0.42, p=001) and 24 hours proteinuria (r=0,33, p=,032), but no correlation was found with activity or chronicity indexes on renal biopsies. A ROC curve for MP-HMGB1+ and renal involvement showed a good discriminative ability (AUC 0.706). A cutoff of 15.7% of MP-HMGB1+ showed the best discrimination threshold with a sensitivity of 63.3% and specificity of 83.3%.ConclusionsIn our cohort of patients with SLE, MP-HMGB1+ was significantly higher in patients with LN and in patients with active disease. Given the multiple implication of HMGB1 in SLE, including the active kidney recruitment of mononuclear phagocytes, we consider that MP-HMGB1+ could be considered as a potential biomarker for LN in SLE patients.References Harris, H. E. et al. HMGB1: A multifunctional alarmin driving autoimmune and inflammatory disease. Nat Rev Rheumatol. 8, 195–202 (2012).Zickert, A. et al. Renal expression and serum levels of high mobility group box 1 protein in lupus nephritis. Arthritis Res Ther. 20;14(1):R36 (2012). AcknowledgementsC. Burbano is recipient of a doctoral scholarship from COLCIENCIAS (call 617–2013). The authors are grateful to the grants “Sostenibilidad and Sistema Universitario de Investigaciones, CODI (2013–05–42869836) from Universidad de Antioquia, and to COLCIENCIAS (...
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