Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that primarily affects the lining of the synovial joints and is associated with progressive disability, premature death, and socioeconomic burdens. A better understanding of how the pathological mechanisms drive the deterioration of RA progress in individuals is urgently required in order to develop therapies that will effectively treat patients at each stage of the disease progress. Here we dissect the etiology and pathology at specific stages: (i) triggering, (ii) maturation, (iii) targeting, and (iv) fulminant stage, concomitant with hyperplastic synovium, cartilage damage, bone erosion, and systemic consequences. Modern pharmacologic therapies (including conventional, biological, and novel potential small molecule disease-modifying anti-rheumatic drugs) remain the mainstay of RA treatment and there has been significant progress toward achieving disease remission without joint deformity. Despite this, a significant proportion of RA patients do not effectively respond to the current therapies and thus new drugs are urgently required. This review discusses recent advances of our  understanding of RA pathogenesis, disease modifying drugs, and provides perspectives on next generation therapeutics for RA

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Latitude gradient influences the age of onset of rheumatoid arthritis : a worldwide survey

The age of onset of rheumatoid arthritis (RA) is an important outcome predictor. Northern countries report an age of RA onset of around 50 years, but apparently, variability exists across different geographical regions. The objective of the present study is to assess whether the age of onset of RA varies across latitudes worldwide. In a proof-of-concept cross-sectional worldwide survey, rheumatologists from preselected cities interviewed 20 consecutive RA patients regarding the date of RA onset (RAO, when the patient first noted a swollen joint). Other studied variables included location of each city, rheumatologist settings, latitudes (10A degrees increments, south to north), longitudes (three regions), intracountry consistency, and countries' Inequality-adjusted Human Development Index (IHDI). Data from 2481 patients (82% females) were obtained from 126 rheumatologists in 77 cities of 41 countries. Worldwide mean age of RAO was 44 +/- 14 years (95% CI 44-45). In 28% of patients, RA began before age 36 years and before age 46 years in 50% of patients. RAO was 8 years earlier around the Tropic of Cancer when compared with northern latitudes (p <0.001, 95% CI 3.5-13). Multivariate analysis showed that females, western cities, and latitudes around the Tropic of Cancer are associated with younger age of RAO (R (2) 0.045, p <0.001). A positive correlation was found between the age of RAO and IHDI (r = 0.7, p <0.01, R (2) 0.5). RA often begins at an early age and onset varies across latitudes worldwide. We postulate that countries' developmental status and their geographical and geomagnetic location influence the age of RAO.Peer reviewe

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Marked-based instruments for managing hazardous chemicals: A review of the literature and future research agenda

We take stock of the lessons learned from using market-based instruments in chemicals management and discuss the potential for increased use of risk-based taxation in the management of pesticides and other hazardous chemicals. Many chemical substances cause significant diffuse emissions when emitted over wide areas at individually low concentrations. These emissions are typically very difficult and costly to control. The targeted chemical may exist in many products as well as in a wide variety of end uses. However, the current regulatory instruments used are primarily bans or quantitative restrictions, which are applied to individual chemicals and for very specific uses. Policy makers in the area of chemicals management have focused almost solely on chemicals with a very steep marginal damage cost curve, leading to low use of price regulations. The growing concerns about cumulative effects and combination effects from lo

AB1218 MATERNAL-FETAL MORBIDITY AND MORTALITY AMONG PREGNANT PATIENTS WITH RHEUMATIC DISEASES IN THE CLINIC OF PREGNANCY AND ARTHRITIS OF THE SALVADORAN SOCIAL SECURITY INSTITUTE

Background:Connective tissue diseases are more frequent among women in childbearing age. In the past, it was not recommended for these women to get pregnant because of the risk of adverse pregnancy outcomes.Objectives:The aim of this study is to compare the morbidity and mortality between pregnant patients with rheumatic diseases and pregnant patients without rheumatic diseases in El Salvador.Methods:A case control study was conducted atthe Clinic of Pregnancy and Arthritisand the1° de Mayo Hospital, both centers belong to theSalvadoran Social Security Institute. Clinical files were reviewed retrospectively and some of the data were collected during the clinical visit to each center. We included pregnant patients with rheumatic diseases of the Clinic of Pregnancy and Arthritis; the control group was randomly selected with a ratio 1:1 within pregnant patients without rheumatic diseases of the 1° de Mayo Hospital, between January 2016 and June 2019. A complication was defined as any event that required hospital admission. We used logistic regression to analyze univariable and multivariable associations to compare pregnancy outcomes between groups.Results:During the study period, 230 patients were randomly included in both, the study group and the control group, with a ratio 1:1. The mean age for the study group was 32 (27-35) years, which was relatively older than the control group, 28 (24-32) years. The mean pregnancy among both groups was 2 per patient. The most common rheumatic diseases in the study group were Rheumatoid arthritis (39.1%), Antiphospholipid Syndrome (31.3%) and Generalized Lupus Erythematosus (20%). The average visit to the Rheumatologist during pregnancy in the study group was 3.2. The visits started at a mean of 15.2 + 7.6 weeks of gestational age.Thirty three point nine percent (33.9%) of the study group presented complications during pregnancy (vs 20.9%). Among the patients who presented complications, 9 of them (7.8%) had more than one complication during pregnancy. There were 44.3% cesarean deliveries in the study group compared with 22.6% in the control group, OR 2.1 (1.5-4.8) p=0.001. There were 16% of preterm deliveries between 34-37 weeks of gestational age in the study group compared to 10% in the control group, OR 2.2 (0.9-4.8) p=0.063. Preterm deliveries before 34 weeks of gestational age in the study group were 18% compared to 3% in the control group, OR 6.9 (2.3-20-9) p=0.001. There were 6 cases of spontaneous abortion in the study group and none in the control group. Thirty four percent (34%) of cases with low birth weight (&lt;2.5kg) were found in the study group compared to 14% in the control group, OR 3.4 (1.6-6.1) p=0.001.Conclusion:The most common rheumatic diseases among pregnant patients were Rheumatoid Arthritis, Antiphospholipid syndrome and Generalized Lupus Erythematosus.Having a rheumatic disease was more associated with cesarean delivery, preterm delivery between 34 and 37 weeks of gestational age, and low birth weight.References:[1]M. Gayed, C. Gordon. Pregnancy and rheumatic diseases. Rheumatology 2007;46:1634–1640.[2]Y A de Man, et al. Annals of Rheumatic Diseases. 2008. 10.1136Disclosure of Interests:None declared</jats:sec

Value of Biomarkers in the Prevention of Rheumatoid Arthritis

Recent diagnostic advances allow to identify persons in a pre-symptomatic stage of rheumatoid arthritis (RA), opening the way for a preventive therapeutic intervention, which may potentially be curative. We review and discuss existing biomarkers predictive of future onset of RA. A responsible use of biomarkers in clinical settings will require an integration of blood-based tests, imaging techniques, clinical history, environmental risk factors, and family history