José Canas da Silva

A preliminary algorithm introducing immunogenicity assessment in the management of patients with RA receiving tumour necrosis factor inhibitor therapies

Introduction Clinical remission is today the treatment goal for rheumatoid arthritis (RA), which requires fast and assertive therapeutic decisions for a tight control of disease activity. Few objective parameters are available to guide clinical decisions, particularly in switcher patients. We designed a preliminary algorithm introducing immunogenicity assessment in the current approach to patients with RA receiving tumour necrosis factor inhibitors (TNFi). Objective To evaluate the concordance between the new algorithm and current clinical practice, comparing the effectiveness of ‘immunogenicity-based’ versus ‘empirical-based’ switches in a cohort of patients with established RA receiving biologics. Methods EULAR therapeutic response was evaluated in 105 patients with RA (naive or switchers) over one year, through generalised estimation equation (GEE) analyses. Serum drug trough levels were assessed by ELISA and antidrug antibodies (ADAb) by Bridging ELISA. Results During follow-up, 48.6% of patients had therapeutic decisions concordant with the proposed algorithm (Group A), and 51.4% had discordant decisions (Group B). One year after the therapeutic decision, patients from Group A had a higher probability of achieving response (OR=7.91, p<0.001, 95% CI 3.27 to 19.13) and low disease activity (OR=9.77, p<0.001, 95% CI 4.69 to 20.37) than patients in Group B. Conclusions Immunogenicity assessment might help to optimise therapeutic decisions, leading to a better control of disease activity with significantly better clinical outcomes in patients with RA receiving TNFi.

Contribution for new genetic markers of rheumatoid arthritis activity and severity: sequencing of the tumor necrosis factor-alpha gene promoter

The objective of this study was to assess whether clinical measures of rheumatoid arthritis activity and severity were influenced by tumor necrosis factor-alpha (TNF-α) promoter genotype/haplotype markers. Each patients disease activity was assessed by the disease activity score using 28 joint counts (DAS28) and functional capacity by the Health Assessment Questionnaire (HAQ) score. Systemic manifestations, radiological damage evaluated by the Sharp/van der Heijde (SvdH) score, disease-modifying anti-rheumatic drug use, joint surgeries, and work disability were also assessed. The promoter region of the TNF-α gene, between nucleotides -1,318 and +49, was sequenced using an automated platform. Five hundred fifty-four patients were evaluated and genotyped for 10 single-nucleotide polymorphism (SNP) markers, but 5 of these markers were excluded due to failure to fall within Hardy-Weinberg equilibrium or to monomorphism. Patients with more than 10 years of disease duration (DD) presented significant associations between the -857 SNP and systemic manifestations, as well as joint surgeries. Associations were also found between the -308 SNP and work disability in patients with more than 2 years of DD and radiological damage in patients with less than 10 years of DD. A borderline effect was found between the -238 SNP and HAQ score and radiological damage in patients with 2 to 10 years of DD. An association was also found between haplotypes and the SvdH score for those with more than 10 years of DD. An association was found between some TNF-α promoter SNPs and systemic manifestations, radiological progression, HAQ score, work disability, and joint surgeries, particularly in some classes of DD and between haplotypes and radiological progression for those with more than 10 years of DD.

The prospective impact of food pricing on improving dietary consumption: A systematic review and meta-analysis

Background While food pricing is a promising strategy to improve diet, the prospective impact of food pricing on diet has not been systematically quantified. Objective To quantify the prospective effect of changes in food prices on dietary consumption. Design We systematically searched online databases for interventional or prospective observational studies of price change and diet; we also searched for studies evaluating adiposity as a secondary outcome. Studies were excluded if price data were collected before 1990. Data were extracted independently and in duplicate. Findings were pooled using DerSimonian-Lairds random effects model. Pre-specified sources of heterogeneity were analyzed using meta-regression; and potential for publication bias, by funnel plots, Beggs and Eggers tests. Results From 3,163 identified abstracts, 23 interventional studies and 7 prospective cohorts with 37 intervention arms met inclusion criteria. In pooled analyses, a 10% decrease in price (i.e., subsidy) increased consumption of healthful foods by 12% (95%CI = 10–15%; N = 22 studies/intervention arms) whereas a 10% increase price (i.e. tax) decreased consumption of unhealthful foods by 6% (95%CI = 4–8%; N = 15). By food group, subsidies increased intake of fruits and vegetables by 14% (95%CI = 11–17%; N = 9); and other healthful foods, by 16% (95%CI = 10–23%; N = 10); without significant effects on more healthful beverages (-3%; 95%CI = -16-11%; N = 3). Each 10% price increase reduced sugar-sweetened beverage intake by 7% (95%CI = 3–10%; N = 5); fast foods, by 3% (95%CI = 1–5%; N = 3); and other unhealthful foods, by 9% (95%CI = 6–12%; N = 3). Changes in price of fruits and vegetables reduced body mass index (-0.04 kg/m2 per 10% price decrease, 95%CI = -0.08–0 kg/m2; N = 4); price changes for sugar-sweetened beverages or fast foods did not significantly alter body mass index, based on 4 studies. Meta-regression identified direction of price change (tax vs. subsidy), number of intervention components, intervention duration, and study quality score as significant sources of heterogeneity (P-heterogeneity<0.05 each). Evidence for publication bias was not observed. Conclusions These prospective results, largely from interventional studies, support efficacy of subsidies to increase consumption of healthful foods; and taxation to reduce intake of unhealthful beverages and foods. Use of subsidies and combined multicomponent interventions appear most effective.

Hemorheological parameters are related to subclinical atherosclerosis in systemic lupus erythematosus and rheumatoid arthritis patients

OBJECTIVES Rheological characteristics of blood are strongly linked to atherothrombosis in the general population, but its contribution to atherosclerosis in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) is currently unclear. This work examines the relationship between blood rheology, traditional cardiovascular (CV) risk factors, inflammation and subclinical atherosclerosis in SLE and RA. METHODS Whole blood viscosity (WBV), plasma viscosity (PV), erythrocyte deformability (ED), aggregation (EA) and erythrocyte NO production were measured in 197 patients (96 SLE and 101 RA) and compared to 97 controls, all females without previous CV events. Clinical information was obtained and fasting lipids and acute phase reactants were measured. The relationship between hemorheological parameters, CV risk factors and inflammation was assessed in patients and the impact of these variables on carotid intima-media thickness (cIMT) was evaluated in univariate followed by multivariate regression analyses. RESULTS WBV and ED are significantly lower in patients, while EA is elevated as compared with controls. Hemorheological disturbances correlate with CV risk factors and markers of inflammation and are more profound in patients with metabolic syndrome. Multivariable analysis showed that menopause (OR 34.72, 95%CI 4.44-271.77), obesity (OR 4.09, 95%CI 1.00-16.68) and WBV (OR 3.98; 95%CI 1.23-12.83) are positively associated whereas current corticosteroid dose (OR 0.87; 95%CI 0.78-0.98), and erythrocyte NO production (OR 0.16; 95%CI 0.05-0.52) are negatively associated with cIMT. CONCLUSION Disturbed hemorheological parameters in SLE and RA women are related to the presence of CV risk factors and inflammation. WBV and erythrocyte NO are independently associated with the early stages of atherosclerosis.

Interleukin-6 promoter polymorphism −174 G/C is associated with nephritis in Portuguese Caucasian systemic lupus erythematosus patients

Interleukin-6 (IL-6) is a multifunctional cytokine with an important pathophysiological role in systemic lupus erythematosus (SLE). The polymorphism of the IL-6 gene promoter at position −174, which appears to influence the production of this cytokine, has been associated with susceptibility to some rheumatic diseases. The aim of this study is to investigate whether the IL-6 −174 G/C polymorphism associates with lupus susceptibility or affects disease characteristics in Portuguese patients with SLE. The association between −174 G/C and lupus diagnosis was studied in 115 adult SLE patients (95.7% females) and 152 healthy controls (94.7% females), all Caucasians. There were no significant differences in genotype or allele frequency between patients and controls. The −174 C/C genotype was independently associated with renal disease and the C allele with the presence of irreversible damage. The IL-6 gene promoter polymorphism at position −174 does not contribute to SLE susceptibility in Portuguese Caucasian patients but may predispose to specific manifestations of the disease.

Early vascular alterations in SLE and RA patients--a step towards understanding the associated cardiovascular risk.

Accelerated atherosclerosis represents a major problem in both systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients, and endothelial damage is a key feature of atherogenesis. We aimed to assess early endothelial changes in SLE and RA female patients (127 SLE and 107 RA) without previous CV events. Biomarkers of endothelial cell activation (intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), thrombomodulin (TM), and tissue factor (TF)) were measured and endothelial function was assessed using peripheral artery tonometry. Reactive hyperemia index (RHI), an indicator of microvascular reactivity, and augmentation index (AIx), a measure of arterial stiffness, were obtained. In addition, traditional CV risk factors, disease activity and medication were determined. Women with SLE displayed higher sICAM-1 and TM and lower TF levels than women with RA (p = 0.001, p<0.001 and p<0.001, respectively). These differences remained significant after controlling for CV risk factors and medication. Serum levels of vascular biomarkers were increased in active disease and a moderate correlation was observed between sVCAM-1 levels and lupus disease activity (rho = 0.246) and between TF levels and RA disease activity (rho = 0.301). Although RHI was similar across the groups, AIx was higher in lupus as compared to RA (p = 0.04). Also in active SLE, a trend towards poorer vasodilation was observed (p = 0.06). In conclusion, women with SLE and RA present with distinct patterns of endothelial cell activation biomarkers not explained by differences in traditional CV risk factors. Early vascular alterations are more pronounced in SLE which is in line with the higher CV risk of these patients.

DAS28, CDAI and SDAI cut-offs do not translate the same information: results from the Rheumatic Diseases Portuguese Register Reuma.pt

OBJECTIVES . The 28-joint DAS (DAS28), clinical disease activity index (CDAI) and simplified disease activity index (SDAI) are indices frequently used to assess disease activity in RA patients. Cut-off values were defined to classify the states of RA disease activity: remission, low, moderate and high. The aim of this work was to assess disease activity states classified by DAS28, CDAI and SDAI and to analyse their agreement in the Rheumatic Diseases Portuguese Register Reuma.pt. METHODS . A total of 2795 patients and 14 440 visits were selected from Reuma.pt for analysis. Pearsons correlation coefficients (PCCs) were calculated for the three indices. McNemars chi-squared tests, PCCs and kappa statistics were performed to analyse and compare the distribution of visits among all disease activity states and indices. RESULTS A strong correlation was found between the three indices throughout the 14 440 visits: r = 0.874 for DAS28/CDAI, r = 0.877 for DAS28/SDAI and r = 0.984 for CDAI/SDAI (all PCCs with P < 0.0001). However, when categorization in the different disease activity states was analysed, McNemars chi-squared tests and PCCs revealed significant disagreement between the cut-offs of the three indices. CONCLUSION DAS28, CDAI and SDAI cut-offs do not translate into the same clinical information in Reuma.pt. Although this might be expected for the original DAS28 cut-offs, when compared with CDAI and SDAI significant disagreement was also found for the DAS28 modified cut-offs. For visits where patients are in CDAI or SDAI remission, we also find disagreement between these two indices, which may contradict previous conclusions that acute phase reactants add little to composite disease activity indices for RA.

TRAF1/C5 but Not PTPRC Variants Are Potential Predictors of Rheumatoid Arthritis Response to Anti-Tumor Necrosis Factor Therapy

Background. The aim of our work was to replicate, in a Southern European population, the association reported in Northern populations between PTPRC locus and response to anti-tumor necrosis factor (anti-TNF) treatment in rheumatoid arthritis (RA). We also looked at associations between five RA risk alleles and treatment response. Methods. We evaluated associations between anti-TNF treatment responses assessed by DAS28 change and by EULAR response at six months in 383 Portuguese patients. Univariate and multivariate linear and logistic regression analyses were performed. In a second step to confirm our findings, we pooled our population with 265 Spanish patients. Results. No association was found between PTPRC rs10919563 allele and anti-TNF treatment response, neither in Portuguese modeling for several clinical variables nor in the overall population combining Portuguese and Spanish patients. The minor allele for RA susceptibility, rs3761847 SNP in TRAF1/C5 region, was associated with a poor response in linear and logistic univariate and multivariate regression analyses. No association was observed with the other allellic variants. Results were confirmed in the pooled analysis. Conclusion. This study did not replicate the association between PTPRC and the response to anti-TNF treatment in our Southern European population. We found that TRAF1/C5 risk RA variants potentially influence anti-TNF treatment response.

Predictors of damage progression in Portuguese patients with systemic lupus erythematosus.

Patients with systemic lupus erythematosus (SLE) have a longer life expectancy. The occurrence of irreversible damage has become a major concern. The present study assessed damage progression in patients with SLE over a 2‐year period and identified baseline features associated with damage accrual. Two hundred and twenty‐one patients that fulfilled criteria for SLE and had a follow‐up longer than 6 months were enrolled. Demographic, clinical, and immunological data were collected at baseline. Accumulated organ damage was scored using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index (SDI). Patients were prospectively followed and SDI assessment repeated at 2 years. At baseline 72 patients (33%) presented some irreversible damage, and after 2 years 53 had accrued new damage. The mean SDI for the whole cohort increased from 0.582 to 0.980. Damage progression was higher in ocular, cardiovascular, and musculoskeletal systems. Older age [OR = 1.045; 95% confidence interval (CI) 1.021–1.069; P= 0.03], presence of antiphospholipid antibodies (OR = 3.047; 95% CI 1.169–7.941; P= 0.02), steroid use (OR = 6.401; 95% CI 1.601–25.210; P= 0.008), azathioprine use (OR = 3.501; CI 1.224–10.012; P= 0.01), and hypertension (OR = 3.825; 95% CI 1.490–9.820; P= 0.005) were predictors of damage progression in multivariate analysis. Overall SDI increased over time, with some systems being affected more frequently. Demographic and clinical characteristics, co‐morbidity, and treatment options may contribute to irreversible damage. It is necessary to determine whether the control of modifiable factors (e.g., hypertension and judicious use of medications) might prevent damage progression in SLE patients.

Effect of comedication with conventional synthetic DMARDs on TNF inhibitors‐retention in patients with spondyloarthritis: A prospective cohort

To evaluate whether use of comedication with conventional synthetic disease‐modifying antirheumatic drugs (csDMARDs) influences the retention of tumor necrosis factor inhibitors (TNFi) in patients with spondyloarthritis (SpA).