Successful Optimization of Adalimumab Therapy in Refractory Uveitis Due to Behçet's Disease.

PURPOSE: To assess efficacy, safety, and cost-effectiveness of adalimumab (ADA) therapy optimization in a large series of patients with uveitis due to Behçet disease (BD) who achieved remission after the use of this biologic agent. DESIGN: Open-label multicenter study of ADA-treated patients with BD uveitis refractory to conventional immunosuppressants. SUBJECTS: Sixty-five of 74 patients with uveitis due to BD, who achieved remission after a median ADA duration of 6 (range, 3-12) months. ADA was optimized in 23 (35.4%) of them. This biologic agent was maintained at a dose of 40 mg/subcutaneously/2 weeks in the remaining 42 patients. METHODS: After remission, based on a shared decision between the patient and the treating physician, ADA was optimized. When agreement between patient and physician was reached, optimization was performed by prolonging the ADA dosing interval progressively. Comparison between optimized and nonoptimized patients was performed. MAIN OUTCOME MEASURES: Efficacy, safety, and cost-effectiveness in optimized and nonoptimized groups. To determine efficacy, intraocular inflammation (anterior chamber cells, vitritis, and retinal vasculitis), macular thickness, visual acuity, and the sparing effect of glucocorticoids were assessed. RESULTS: No demographic or ocular differences were found at the time of ADA onset between the optimized and the nonoptimized groups. Most ocular outcomes were similar after a mean ± standard deviation follow-up of 34.7±13.3 and 26±21.3 months in the optimized and nonoptimized groups, respectively. However, relevant adverse effects were only seen in the nonoptimized group (lymphoma, pneumonia, severe local reaction at the injection site, and bacteremia by Escherichia coli, 1 each). Moreover, the mean ADA treatment costs were lower in the optimized group than in the nonoptimized group (6101.25 euros/patient/year vs. 12 339.48; P < 0.01). CONCLUSION: ADA optimization in BD uveitis refractory to conventional therapy is effective, safe, and cost-effective.

Role of mTOR inhibitors for the control of viral infection in solid organ transplant recipients.

Appropriate post-transplant immunosuppressive regimens that avoid acute rejection, while reducing risk of viral reactivation, have been sought, but remain a chimera. Recent evidence suggesting potential regulatory and antiviral effects of mammalian target of rapamycin inhibitors (mTORi) is of great interest. Although the concept of an immunosuppressive drug with antiviral properties is not new, little effort has been made to put the evidence together to assess the management of immunosuppressive therapy in the presence of a viral infection. This review was developed to gather the evidence on antiviral activity of the mTORi against the viruses that most commonly reactivate in adult solid organ recipients: cytomegalovirus (CMV), polyomavirus, Epstein-Barr virus (EBV), human herpesvirus 8 (HHV8), and hepatitis C virus (HCV). A rapid review methodology and evaluation of quality and consistency of evidence based on the GRADE system was used. The existing literature was variable in nature, although indicating a potential advantage of mTORi in CMV, polyomavirus, and HHV8 infection, and a most doubtful relation with EBV and HCV infection. Several recommendations about the management of these infections are presented that can change certain current patterns of immunosuppression and help to improve the prognosis of the direct and indirect effects of viral infection in solid organ recipients.

Anti-TNF-α therapy in patients with refractory uveitis due to Behçet's disease: a 1-year follow-up study of 124 patients.

OBJECTIVE: The aim of this study was to assess the efficacy of anti-TNF-α therapy in refractory uveitis due to Behçet's disease (BD). METHODS: We performed a multicentre study of 124 patients with BD uveitis refractory to conventional treatment including high-dose corticosteroids and at least one standard immunosuppressive agent. Patients were treated for at least 12 months with infliximab (IFX) (3-5 mg/kg at 0, 2 and 6 weeks and then every 4-8 weeks) or adalimumab (ADA) (usually 40 mg every 2 weeks). The main outcome measures were degree of anterior and posterior chamber inflammation, visual acuity, macular thickness and immunosuppression load. RESULTS: Sixty-eight men and 56 women (221 affected eyes) were studied. The mean age was 38.6 years (s.d. 10.4). HLA-B51 was positive in 66.1% of patients and uveitis was bilateral in 78.2%. IFX was the first biologic agent in 77 cases (62%) and ADA was first in 47 (38%). In most cases anti-TNF-α drugs were used in combination with conventional immunosuppressive drugs. At the onset of anti-TNF-α therapy, anterior chamber and vitreous inflammation was observed in 57% and 64.4% of patients, respectively. In both conditions the damage decreased significantly after 1 year. At baseline, 50 patients (80 eyes) had macular thickening [optical coherence tomography (OCT) >250 µm] and 35 (49 eyes) had cystoid macular oedema (OCT>300 µm) that improved from 420 µm (s.d. 119.5) at baseline to 271 µm (s.d. 45.6) at month 12 (P < 0.01). The best-corrected visual acuity and the suppression load also showed significant improvement. After 1 year of follow-up, 67.7% of patients were inactive. Biologic therapy was well tolerated in most cases. CONCLUSION: Anti-TNF-α therapy is effective and relatively safe in refractory BD uveitis.

GHG Emissions from Dairy Small Ruminants in Castilla-La Mancha (Spain), Using the ManleCO2 Simulation Model.

The first goal of this work was the description of a model addressed to quantify the carbon footprint in Spanish autochthonous dairy sheep farms (Manchega group), foreign dairy sheep farms (foreigners group: Lacaune and Assaf breeds), and Spanish autochthonous dairy goat farms (Florida group). The second objective was to analyze the GHG emission mitigation potential of 17 different livestock farming practices that were implemented by 36 different livestock farms, in terms of CO2e per hectare (ha), CO2e per livestock unit (LU), and CO2e per liter of fat- and protein-corrected milk (FPCM). The study showed the following results: 1.655 kg CO2e per ha, 6.397 kg CO2e per LU, and 3.78 kg CO2e per liter of FPCM in the Manchega group; 12.634 kg CO2e per ha, 7.810 CO2e kg per LU, and 2.77 kg CO2e per liter of FPCM in the Foreigners group and 1.198 kg CO2e per ha, 6.507 kg CO2e per LU, and 3.06 kg CO2e per liter of FPCM in Florida group. In summary, purchasing off-farm animal feed would increase emissions by up to 3.86%. Conversely, forage management, livestock inventory, electrical supply, and animal genetic improvement would reduce emissions by up to 6.29%, 4.3%, 3.52%, and 0.8%, respectively; finally, an average rise of 2 °C in room temperature would increase emissions by up to 0.62%.

Comparative Study of Infliximab Versus Adalimumab in Refractory Uveitis due to Behçet's Disease: National Multicenter Study of 177 Cases.

OBJECTIVE: To compare the efficacy of infliximab (IFX) versus adalimumab (ADA) as a first-line biologic drug over 1 year of treatment in a large series of patients with refractory uveitis due to Behçet's disease (BD). METHODS: We conducted an open-label multicenter study of IFX versus ADA for BD-related uveitis refractory to conventional nonbiologic treatment. IFX or ADA was chosen as the first-line biologic agent based on physician and patient agreement. Patients received 3-5 mg/kg intravenous IFX at 0, 2, and 6 weeks and every 4-8 weeks thereafter, or 40 mg subcutaneous ADA every other week without a loading dose. Ocular parameters were compared between the 2 groups. RESULTS: The study included 177 patients (316 affected eyes), of whom 103 received IFX and 74 received ADA. There were no significant baseline differences between treatment groups in main demographic features, previous therapy, or ocular sign severity. After 1 year of therapy, we observed an improvement in all ocular parameters in both groups. However, patients receiving ADA had significantly better outcomes in some parameters, including improvement in anterior chamber inflammation (92.31% versus 78.18% for IFX; P = 0.06), improvement in vitritis (93.33% versus 78.95% for IFX; P = 0.04), and best-corrected visual acuity (mean ± SD 0.81 ± 0.26 versus 0.67 ± 0.34 for IFX; P = 0.001). A nonsignificant difference was seen for macular thickness (mean ± SD 250.62 ± 36.85 for ADA versus 264.89 ± 59.74 for IFX; P = 0.15), and improvement in retinal vasculitis was similar between the 2 groups (95% for ADA versus 97% for IFX; P = 0.28). The drug retention rate was higher in the ADA group (95.24% versus 84.95% for IFX; P = 0.042). CONCLUSION: Although both IFX and ADA are efficacious in refractory BD-related uveitis, ADA appears to be associated with better outcomes than IFX after 1 year of follow-up.

The combined effect of pre-transplant triglyceride levels and the type of calcineurin inhibitor in predicting the risk of new onset diabetes after renal transplantation.

BACKGROUND: Insulin resistance precedes overt diabetes in the general population and hypertriglyceridemia is a reliable marker of the disorder. Thus, patients in the waiting list with hypertriglyceridemia may be at risk for new-onset diabetes after transplantation (NODAT). Objectives. We investigate whether pre-transplant triglyceride (TG) levels are a risk factor for NODAT and whether they exert a combined effect with the type of calcineurin inhibitor (CNI). METHODS: We analysed 314 consecutive non-diabetic recipients [215 cyclosporine A (CsA); 99 tacrolimus (Tacro)] transplanted between 1999 and 2003 with a mean follow-up of 34 months. Outcome was NODAT defined by ADA criteria. RESULTS: NODAT developed in 81 recipients (25.8%). Multivariate analysis which included a propensity score for factors determining CNI allocation showed that age (OR: 1.06; 95% CI: 1.03-1.09), pre-transplant BMI (OR: 1.1; 95% CI: 1.02-1.17),TG levels (OR: 1.3 per 50 mg/dl increment, 95% CI: 1.07-1.6) and treated acute rejection (OR: 4.8, 95% CI: 3-11), but not the type of CNI, were independent risk factors for NODAT. A significant interaction between pre-transplant TG and type of CNI was observed. Using CsA as the reference, the combination of Tacro plus pre-transplant hypertriglyceridemia (>/=200 mg/dl) showed an OR of 3.26 (1.4-7.8) to develop NODAT, contrasting with an OR of 0.75 (0.34-1.6) in Tacro recipients with pre-transplant TG levels <200 mg/dl. CONCLUSION: Pre-transplant hypertriglyceridemia was a risk factor for NODAT only in recipients treated with Tacro; it highlights the importance of pre-transplant insulin resistance in the pathogenesis of NODAT.

Efficacy and Safety of an Aflibercept Treat-and-Extend Regimen in Treatment-Naïve Patients with Macular Oedema Secondary to Central Retinal Vein Occlusion (CRVO): A Prospective 12-Month, Single-Arm, Multicentre Trial.

OBJECTIVES: To evaluate efficacy and safety of an aflibercept treat-and-extend (TAE) regimen in patients with macular oedema (MO) secondary to central retinal vein occlusion (CRVO). DESIGN SETTING AND PATIENTS: Phase IV, prospective, open-label, single-arm trial in 11 Spanish hospitals. Treatment-naïve patients with <6 month diagnosis of MO secondary to CRVO and best-corrected visual acuity (BCVA) of 73-24 ETDRS letters were included between 23 January 2015 and 17 March 2016. INTERVENTION: Intravitreal aflibercept 2 mg monthly (3 months) followed by proactive individualized dosing. MAIN OUTCOMES: Mean change in BCVA after 12 months. RESULTS: 24 eyes (24 patients) were included; mean (SD) age: 62.8 (15.0) years; 54.2% male; median (IQR) time since diagnosis: 7.6 (3.0, 15.2) days. Mean BCVA scores significantly improved between baseline (56.0 (16.5)) and Month 12 (74.1 (17.6)); mean (95% CI) change: 14.8 (8.2, 21.4); P=0.0001. Twelve (50.0%) patients gained ≥15 ETDRS letters. Foveal thickness improved between baseline (mean: 569.4 (216.8) µm) and Month 12 (mean 257.4 (48.4) µm); P < 0.0001. At Month 12, 8.3% patients had MO. The mean (SD) number of injections: 8.3 (3.0). No treatment-related AEs were reported. Five (20.8%) patients experienced ocular AEs. Two nonocular serious AEs were reported. CONCLUSIONS: An aflibercept TAE regimen improves visual acuity in patients with MO secondary to CRVO over 12 months with good tolerability.

Randomized Controlled Trial Assessing the Impact of Tacrolimus Versus Cyclosporine on the Incidence of Posttransplant Diabetes Mellitus.

INTRODUCTION: Despite the high incidence of posttransplant diabetes mellitus (PTDM) among high-risk recipients, no studies have investigated its prevention by immunosuppression optimization. METHODS: We conducted an open-label, multicenter, randomized trial testing whether a tacrolimus-based immunosuppression and rapid steroid withdrawal (SW) within 1 week (Tac-SW) or cyclosporine A (CsA) with steroid minimization (SM) (CsA-SM), decreased the incidence of PTDM compared with tacrolimus with SM (Tac-SM). All arms received basiliximab and mycophenolate mofetil. High risk was defined by age >60 or >45 years plus metabolic criteria based on body mass index, triglycerides, and high-density lipoprotein-cholesterol levels. The primary endpoint was the incidence of PTDM after 12 months. RESULTS: The study comprised 128 de novo renal transplant recipients without pretransplant diabetes (Tac-SW: 44, Tac-SM: 42, CsA-SM: 42). The 1-year incidence of PTDM in each arm was 37.8% for Tac-SW, 25.7% for Tac-SM, and 9.7% for CsA-SM (relative risk [RR] Tac-SW vs. CsA-SM 3.9 [1.2-12.4; P = 0.01]; RR Tac-SM vs. CsA-SM 2.7 [0.8-8.9; P = 0.1]). Antidiabetic therapy was required less commonly in the CsA-SM arm (P = 0.06); however, acute rejection rate was higher in CsA-SM arm (Tac-SW 11.4%, Tac-SM 4.8%, and CsA-SM 21.4% of patients; cumulative incidence P = 0.04). Graft and patient survival, and graft function were similar among arms. CONCLUSION: In high-risk patients, tacrolimus-based immunosuppression with SM provides the best balance between PTDM and acute rejection incidence.

Prevalence and clinical characteristics of renal transplant patients with true resistant hypertension.

OBJECTIVE: Arterial hypertension is a prevalent complication that occurs in 75-90% of kidney-transplant recipients. Data about resistant arterial hypertension are scarce. The aim of this multicenter, cross-sectional, and observational study was to assess the prevalence and the clinical features of true resistant hypertension among renal-transplant patients. METHODS: Eligible patients included hypertensive cadaveric kidney-transplant recipients aged below 70 years, with functioning kidney for at least 1 year, and with an estimated glomerular filtration rate at least 30 ml/min per 1.73 m and serum creatinine below 2.5 mg/dl. Recorded data included demographic characteristics, office blood pressure, and ambulatory blood pressure monitoring and laboratory investigations. A total of 868 patients (mean age 53.2 ±â€Š11.6 years) were included. RESULTS: Mean systolic and diastolic office blood pressure was 140.2 ±â€Š18 and 80.4 ±â€Š10 mmHg, respectively. Mean 24-h ambulatory SBP and DBP was 131.5 ±â€Š14 and 77.4 ±â€Š8.7 mmHg and the prevalence of true resistant hypertension was 18.9%. Those with resistant hypertension were older and men, with a worse cardiovascular risk profile and history of cardiovascular disease. Apart from this, these patients had worse graft function and treatment with steroids. CONCLUSIONS: The present study provides evidence about the prevalence of true resistant hypertension in renal-transplant patients. It also shows the very high cardiovascular risk of true resistant hypertension and the elevated association of this condition with renal failure, organ damage, and history of cardiovascular events.

Calcium current components in intact and dissociated adult mouse sympathetic neurons.

We examined which types of high threshold Ca(2+) channels are activated by depolarization in intact and dissociated sympathetic neurons from adult mouse superior cervical ganglia (SCG). Ba(2+) currents were recorded with microelectrodes and discontinuous voltage clamp from neurons in intact ganglia, and using the perforated patch clamp technique in dissociated cells. Peak current was larger in intact neurons, although the voltage dependence was similar. Successive application of omega-conotoxin GVIA, omega-conotoxin MVIIC and nifedipine revealed that the total current in intact cells was composed by 29% N-type, 13% P/Q-type, 32% L-type and 26% resistant to blockade (R-type). In dissociated cells, the N component was larger and the L component smaller, whereas P/Q-type and R-type were similar. Peak currents evoked with an action potential waveform instead of a square pulse were larger in both preparations but the proportions of each component were similar. We conclude that dissociating and culturing somata results in data that only partially reflect the situation in intact neurons. Assuming that the main effect of dissociation is the removal of mature dendritic membrane, the data suggest that L channels are more abundant on dendrites and N channels on the soma of intact sympathetic neurons, whereas P/Q and R channels may be uniformly distributed over the cell surface. Finally, in intact SCG neurons from rats, the proportions of current evoked by a pulse were: 49% N-type, 11% P/Q-type, 21% L-type and 20% R-type when nifedipine was applied last, suggesting that there are species differences in the expression of L and N channels.

Adaptation in the visual cortex: influence of membrane trajectory and neuronal firing pattern on slow afterpotentials.

The input/output relationship in primary visual cortex neurons is influenced by the history of the preceding activity. To understand the impact that membrane potential trajectory and firing pattern has on the activation of slow conductances in cortical neurons we compared the afterpotentials that followed responses to different stimuli evoking similar numbers of action potentials. In particular, we compared afterpotentials following the intracellular injection of either square or sinusoidal currents lasting 20 seconds. Both stimuli were intracellular surrogates of different neuronal responses to prolonged visual stimulation. Recordings from 99 neurons in slices of visual cortex revealed that for stimuli evoking an equivalent number of spikes, sinusoidal current injection activated a slow afterhyperpolarization of significantly larger amplitude (8.5 ± 3.3 mV) and duration (33 ± 17 s) than that evoked by a square pulse (6.4 ± 3.7 mV, 28 ± 17 s; p<0.05). Spike frequency adaptation had a faster time course and was larger during plateau (square pulse) than during intermittent (sinusoidal) depolarizations. Similar results were obtained in 17 neurons intracellularly recorded from the visual cortex in vivo. The differences in the afterpotentials evoked with both protocols were abolished by removing calcium from the extracellular medium or by application of the L-type calcium channel blocker nifedipine, suggesting that the activation of a calcium-dependent current is at the base of this afterpotential difference. These findings suggest that not only the spikes, but the membrane potential values and firing patterns evoked by a particular stimulation protocol determine the responses to any subsequent incoming input in a time window that spans for tens of seconds to even minutes.

Anemia control in renal transplant recipients receiving continuous erythropoietin receptor activator (C.E.R.A.) treatment: the AnemiaTrans Study.

INTRODUCTION: Continuous erythropoietin receptor activator (C.E.R.A.) effectively enables anemia control in patients with chronic kidney disease, but little information is available in renal transplant recipients. The authors aimed to evaluate the effect of C.E.R.A. under clinical practice conditions on anemia control in renal transplant recipients. METHODS: This was a multicenter, retrospective, observational study carried out in adult renal transplant patients in the immediate posttransplant period and at late posttransplant period receiving C.E.R.A. in clinical practice. Patients' data were retrieved from their medical charts at baseline and months 1, 3, and 6. RESULTS: A total of 318 evaluable patients were enrolled into the study: 32 in the immediate posttransplant period and 286 at late posttransplant period (erythropoiesis-stimulating agent [ESA]-naïve, n = 44; converting from other ESAs, n = 242). Patients in the immediate posttransplant period experienced a significant increase in hemoglobin (Hb) levels from baseline to month 1 (9.9±1.5 g/dL vs. 11.5±1.4 g/dL; P< 0.001). ESA-naïve patients showed increasing mean Hb levels from baseline to month 6 (10.1±0.7 g/dL vs. 11.7±1.0 g/dL; P < 0.001) and 94.7% achieved Hb ≥11 g/dL during the study. In patients converted from other ESAs, the percentage of patients with Hb between 11-13 g/dL was maintained from baseline to month 6 with no significant differences (61.0% vs. 62.4%). Mean monthly doses of C.E.R.A. at baseline were 134.4±56.4 µg, 81.3±28.1 µg, and 93.0±44.2 µg in immediate posttransplant, ESA-naïve, and converted patients, respectively. C.E.R.A. was well tolerated. CONCLUSION: C.E.R.A. enables anemia control in renal transplant recipients, allowing target Hb levels to be achieved and maintained with doses even below those described in the Summary of Product Characteristics.

Oral propranolol for circumscribed choroidal hemangioma.

INTRODUCTION: Several therapeutic approaches have been developed to treat choroidal hemangioma. However, all these therapies are associated with a potential risk of damaging the overlying retina. CASE REPORT: We report a case of circumscribed choroidal hemangioma (CCH) in a 59-year-old man refractory to laser treatment. Visual acuity was 20/200 and a serous macular detachment was present. The CCH was treated with oral propanolol, whereupon visual acuity improved to 20/20 and the macular detachment resolved without systemic or local adverse effects. DISCUSSION: Propanolol is a ß-blocker commonly used in cardiology that may induce endothelium vasoconstriction and inhibit endothelial proliferation. It has been shown to be effective in infantile facial hemangiomas, and proved safe and effective for the CCH in our patient. Further studies are needed to confirm our observation.

Renal transplantation in patients with hepatitis C virus antibody. A long national experience.

Background. Renal transplantation is the best therapy for patients with hepatitis C virus (HCV) infection with end-stage renal disease. Patient and graft survival are lower in the long term compared with HCV-negative patients. The current study evaluated the results of renal transplantation in Spain in a long period (1990-2002), focusing on graft failure.Methods. Data on the Spanish Chronic Allograft Nephropathy Study Group including 4304 renal transplant recipients, 587 of them with HCV antibody, were used to estimate graft and patient survival at 4 years with multivariate Cox models.Results. Among recipients alive with graft function 1 year post-transplant, the 4-year graft survival was 92.8% in the whole group; this was significantly better in HCV-negative vs HCV-positive patients (94.4% vs 89.5%, P < 0.005). Notably, HCV patients showed more acute rejection, a higher degree of proteinuria accompanied by a diminution of renal function, more graft biopsies and lesions of de novo glomerulonephritis and transplant glomerulopathy. Serum creatinine and proteinuria at 1 year, acute rejection, HCV positivity and systolic blood pressure were independent risk factors for graft loss. Patient survival was 96.3% in the whole group, showing a significant difference between HCV-negative vs HCV-positive patients (96.6% vs 94.5%, P < 0.05). Serum creatinine and diastolic blood pressure at 1 year, HCV positivity and recipient age were independent risk factors for patient death.Conclusions. Renal transplantation is an effective therapy for HCV-positive patients with good survival but inferior than results obtained in HCV-negative patients in the short term. Notably, HCV-associated renal damage appears early with proteinuria, elevated serum creatinine showing chronic allograft nephropathy, transplant glomerulopathy and, less frequently, HCV-associated de novo glomerulonephritis. We suggest that HCV infection should be recognized as a true risk factor for graft failure, and preventive measures could include pre-transplant therapy with interferon.

Impact of cortical network activity on short-term synaptic depression.

Repetitive stimulation of synaptic connections in the cerebral cortex often induces short-term synaptic depression (STD), a property directly related to the probability of transmitter release and critical for the computational properties of the network. In order to explore how spontaneous activity in the network affects this property, we first studied STD in cortical slices that were either silent or that displayed spontaneous rhythmic slow oscillations resembling those recorded during slow wave sleep in vivo. STD was considerably reduced by the occurrence of spontaneous rhythmic activity in the cortical network. Once the rhythmic activity started, depression decreased over time in parallel with the duration and intensity of the ongoing activity until a plateau was reached. Thalamocortical and intracortical synaptic potentials studied in vivo also showed stronger depression in a silent than in an active cortical network, and the depression values in the active cortical network in vivo were indistinguishable from those found in active slices in vitro. We suggest that this phenomenon is due to the different steady states of the synapses in active and in silent networks.