Metabolic syndrome (MS), a cluster of metabolic risk factors, ranging from abdominal obesity, dyslipidaemia, hypertension, type 2 diabetes and non-alcoholic fatty liver disease ...
To evaluate the efficacy and safety of secukinumab in Behçet's patients with active mucocutaneous and articular manifestations refractory to previous treatments.
We retrospectively evaluated 5 ...patients treated with the IL17-inhibitor secukinumab and diagnosed with Behçet according to ISG/ICBD criteria. All patients had active mucocutaneous and articular manifestations refractory to colchicine, conventional DMARDs and at least one anti-TNFα agent. Four patients received secukinumab in the dose of 150 mg/monthly since also fulfilling the criteria for ankylosing spondylitis, while the fifth patient received secukinumab 300 mg/monthly because she met psoriatic arthritis criteria. Achievement of response was based on the number of oral ulcers, BASDAI and ASDAS for articular involvement, and BDCAF for Behçet activity. Complete response was defined as: i) decrease ≥50% in the number of oral ulcers; ii) BASDAI index <4; iii) ASDAS index <1.4; iv) decrease of 50% or more in BDCAF index.
The patient starting secukinumab 300 mg/month successfully achieved complete response within 3 months. Complete response was maintained during all 9-months follow-up. Among the 4 subjects starting secukinumab 150 mg/month, two achieved complete response at month 6, but one relapsed. This patient and the two who not achieved complete response at month 6 were switched to secukinumab 300 mg/month. Within 3 months from the dosage increase, all three subjects successfully (re)achieved complete response.
Our study suggested for the first time that secukinumab (either 150 mg and 300 mg/month) improved active mucocutaneous manifestations refractory to previous treatments, while secukinumab 300 mg/monthly resulted superior in inducing articular and complete response in Behçet's patients.
•Secukinumab is effective for Behçet's mucocutaneous and articular manifestations.•Secukinumab 300 mg is superior to 150 mg for inducing articular and complete response.•Due to secukinumab safety concerns in IBD, attention must be paid in entero-Behçet.
Behçet disease (BD) is a systemic vasculitis with a broad range of organ involvement, characterized by a multisystemic, immune-inflammatory disorder involving vessels of all sizes and often ...complicated by thrombosis. Systemic redox imbalance and circulating neutrophil hyperactivation have been observed in BD patients and are thought to be responsible for impaired coagulation. We here focused on the pathogenetic mechanisms potentially linking immune cell activation and thrombosis, and specifically examined whether neutrophil activation can affect fibrinogen modifications and consequently elicit thrombosis.
Blood samples were collected from 98 consecutive BD patients attending our dedicated Center and from 70 age- and sex-matched healthy controls; in all patients fibrinogen function and structure, fibrin susceptibility to plasmin-lysis, plasma redox status, leukocyte oxidative stress markers, and possible reactive oxygen species sources were examined. Thrombin-catalyzed fibrin formation and fibrin susceptibility to plasmin-induced lysis were significantly impaired in BD patients (P<0.001). These findings were associated with increased plasma oxidative stress markers (P<0.001) and with a marked carbonylation of fibrinogen (P<0.001), whose secondary structure appeared deeply modified. Neutrophils displayed an enhanced NADPH oxidase activity and increased reactive oxygen species production (P<0.001), which significantly correlated with fibrinogen carbonylation level (r(2)=0.33, P<0.0001), residual β-band intensity (r(2)=0.07, P<0.01), and fibrinogen clotting ability (r(2)=0.073, P<0.01) CONCLUSIONS: In BD patients, altered fibrinogen structure and impaired fibrinogen function are associated with neutrophil activation and enhanced reactive oxygen species production whose primary source is represented by neutrophil NADPH oxidase.
Inflammatory bowel disease affects more than 2 million people in Europe, with almost 20% of patients being diagnosed in pediatric age. Patients with inflammatory bowel disease are at increased risk ...of thromboembolic complications which may affect patients' morbidity and mortality. The risk of the most common thromboembolic events, such as deep venous thrombosis and pulmonary embolism, are estimated to be three-fold increased compared to controls, but many other districts can be affected. Moreover, patients with ulcerative colitis and Crohn's disease experience thromboembolic events at a younger age compared to general population. Many factors have been investigated as determinants of the pro-thrombotic tendency such as acquired risk factors or genetic and immune abnormalities, but a unique cause has not been found. Many efforts have been focused on the study of abnormalities in the coagulation cascade, its natural inhibitors and the fibrinolytic system components and both quantitative and qualitative alterations have been demonstrated. Recently the role of platelets and microvascular endothelium has been reviewed, as the possible link between the inflammatory and hemostatic process.
Much is known, but there is also much more to discover, about the actions that thyroid hormones (TH) exert on metabolism. Indeed, despite the fact that thyroid hormones are recognized as one of the ...most important regulators of metabolic rate, much remains to be clarified on which mechanisms control/regulate these actions. Given their actions on energy metabolism and that mitochondria are the main cellular site where metabolic transformations take place, these organelles have been the subject of extensive investigations. In relatively recent times, new knowledge concerning both thyroid hormones (such as the mechanisms of action, the existence of metabolically active TH derivatives) and the mechanisms of energy transduction such as (among others) dynamics, respiratory chain organization in supercomplexes and cristes organization, have opened new pathways of investigation in the field of the control of energy metabolism and of the mechanisms of action of TH at cellular level. In this review, we highlight the knowledge and approaches about the complex relationship between TH, including some of their derivatives, and the mitochondrial respiratory chain.
Thyroid hormones significantly influence energy expenditure by affecting the activity of metabolic active tissues, among which, mammalian brown adipose tissue (BAT) plays a significant role. For a ...long time, the modulation of BAT activity by 3,3',5-triiodo-l-thyronine (T3) has been ascribed to its direct actions on this tissue; however, recent evidence indicates that T3, by stimulating specific brain centers, activates the metabolism of BAT
the sympathetic nervous system. These distinct mechanisms of action are not mutually exclusive. New evidence indicates that 3,5-diiodo-l-thyronine (3,5-T2), a thyroid hormone derivative, exerts thermogenic effects, by influencing mitochondrial activity in metabolically active tissues, such as liver, skeletal muscle, and BAT. At the moment, due to the absence of experiments finalized to render a clear cut discrimination between peripheral and central effects induced by 3,5-T2, it is not possible to exclude that some of the metabolic effects exerted by 3,5-T2 may be mediated centrally. Despite this, some evidence suggests that 3,5-T2 plays a role in adrenergic stimulation of thermogenesis in BAT. This mini-review provides an overview of the effects induced by T3 and 3,5-T2 on BAT thermogenesis, with a focus on data suggesting the involvement of central adrenergic stimulation. These aspects may reveal new perspectives in thyroid physiology and in the control of energy metabolism.
Interleukin (IL)-1 plays a crucial role in the pathogenesis of Adult onset Still's disease (AOSD).
To evaluate the efficacy and safety of anakinra (ANA) and canakinumab (CAN) in a large group of AOSD ...patients.
Data on clinical, serological features, and concomitant treatments were retrospectively collected at baseline and after 3, 6, and 12 months from AOSD patients (Yamaguchi criteria) referred by 18 Italian centers. Pouchot's score was used to evaluate disease severity.
One hundred forty patients were treated with ANA; 4 were subsequently switched to CAN after ANA failure. The systemic pattern of AOSD was identified in 104 (74.2%) of the ANA-treated and in 3 (75%) of the CAN-treated groups; the chronic-articular type of AOSD was identified in 48 (25.8%) of the ANA-treated and in 1 (25%) of the CAN-treated groups. Methotrexate (MTX) was the most frequent disease modifying anti-rheumatic drug (DMARD) used before beginning ANA or CAN 91/140 (75.8%), 2/4 (50%), respectively. As a second-line biologic DMARD therapy in 29/140 (20.7%) of the patients, ANA was found effective in improving all clinical and serological manifestations (
< 0.0001), and Pouchot's score was found to be significantly reduced at all time points (
< 0.0001). No differences in treatment response were identified in the ANA-group when the patients were stratified according to age, sex, disease pattern or mono/combination therapy profile. ANA primary and secondary inefficacy at the 12-month time point was 15/140 (10.7%) and 11/140 (7.8%), respectively. Adverse events (AEs) mainly represented by in situ (28/47, 59.5%) or diffuse (12/47, 25.5%) skin reactions and infections (7/47, 14.8%) were the main causes for discontinuation. Pouchot's score and clinical and serological features were significantly ameliorated at all time points (
< 0.0001) in the CAN-group, and no AEs were registered during CAN therapy. Treatment was suspended for loss of efficacy only in one case (1/4, 25%).
This is the largest retrospective observational study evaluating the efficacy and safety of IL-1 inhibitors in AOSD patients. A good response was noted at 3 months after therapy onset in both the ANA- and CAN-groups. Skin reaction may nevertheless represent a non-negligible AE during ANA treatment.
Whereas the relationship between subclinical atherosclerosis and antiphospholipid syndrome (APS) has been widely investigated, little is known about subclinical atherosclerosis in asymptomatic ...carriers with isolated antiphospholipid antibodies positivity (APP).
Consecutive APP carriers, APS subjects and matched controls were enrolled. Intima-media thickness of the common carotid artery (CCA-IMT) and of the Bulb (Bulb-IMT) and the prevalence of carotid plaques were assessed in all enrolled subjects.
A total of 104 APP carriers, 221 APS subjects, and 325 matched controls were recruited. As compared with controls, APP carriers and APS subjects showed a higher CCA-IMT (0.90 ± 0.24 vs 0.82 ± 0.12, p = 0.014 and 0.93 ± 0.42 vs 0.82 ± 0.12, p < 0.001, respectively), Bulb-IMT (1.10 ± 0.44 vs 0.95 ± 0.18, p = 0.006 and 1.22 ± 0.68 vs 0.95 ± 0.18, p < 0.001, respectively) and an increased prevalence of carotid plaques (33.7% vs 10.2%, p < 0.001 and 38.5% vs 10.2%, p < 0.001, respectively). These results were confirmed stratifying for antibody isotype, after excluding subjects with systemic lupus erythematosus or other autoimmune diseases and after adjusting for major clinical and demographic variables. CCA-IMT, Bulb-IMT and the prevalence of carotid plaques were higher in subjects with high-titer antibodies and progressively increased for an increasing number of positive antibodies.
Similar to APS subjects, APP carriers have enhanced subclinical atherosclerosis, a more severe disease being observed in the presence of high-titer antibodies and multiple antibodies positivity. These data argue for a strict monitoring of subclinical signs of atherosclerosis and of cardiovascular risk factors in asymptomatic APP carriers.
•Carriers of antiphospholipid antibodies (APP) have enhanced carotid atherosclerosis.•Carotid atherosclerosis is more severe in APP with high-titer antibodies.•Carotid atherosclerosis is maximal in APP with multiple antibody positivity.
The pathogenic road map leading to Alzheimer's disease (AD) is still not completely understood; however, a large body of studies in the last few years supports the idea that beside the classic ...hallmarks of the disease, namely the accumulation of amyloid-β (Aβ) and neurofibrillary tangles, other factors significantly contribute to the initiation and the progression of the disease. Among them, mitochondria failure, an unbalanced neuronal redox state, and the dyshomeostasis of endogenous metals like copper, iron, and zinc have all been reported to play an important role in exacerbating AD pathology. Given these factors, the endogenous peptide carnosine may be potentially beneficial in the treatment of AD because of its free-radical scavenger and metal chelating properties.
In this study, we explored the effect of L-carnosine supplementation in the 3xTg-AD mouse, an animal model of AD that shows both Aβ- and tau-dependent pathology.
We found that carnosine supplementation in 3xTg-AD mice promotes a strong reduction in the hippocampal intraneuronal accumulation of Aβ and completely rescues AD and aging-related mitochondrial dysfunctions. No effects were found on tau pathology and we only observed a trend toward the amelioration of cognitive deficits.
Our data indicate that carnosine can be part of a combined therapeutic approach for the treatment of AD.
PDF
