The histone deacetylase, SIRT1, plays a major role in glucose regulation and lipid metabolism. Ammonium Trichloro (dioxoethylene-o,o') Tellurate, AS101, is a potent in vitro and in vivo immunomodulator, with several potential therapeutic applications. AS101 administration resulted in upregulation of SIRT1 protein expression and activity. These effects were associated with decreased levels of serum insulin like growth factor-1 (IGF-1) and of insulin. The properties of AS101 prompted us to investigate its potential therapeutic role in rats with type 2 diabetes (T2D). T2D was induced by a high fat diet combined with a low dose of Streptozotocin (STZ). Treatment with AS101 before manifestation of hyperglycemia, resulted in increased insulin sensitivity, and decreased blood glucose levels, and prevented symptoms of diabetes including defective glucose clearance, fatty liver, and abnormal distribution of insulin-producing beta cells in the pancreas. Treatment after disease emergence resulted in partial restoration of normal glucose homeostasis. Diabetic rats showed a reduction in liver SIRT1 levels. In both treatment regimens the reduction in SIRT1 levels in the liver were blocked by AS101 consumption. Together, these findings demonstrate the therapeutic potential of AS101 for treating T2D, and for reversing impaired fat and glucose metabolism.

Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system (CNS) involving demyelinating and neurodegenerative processes. Several of the major pathological CNS alterations and behavioral deficits of MS are recapitulated in the experimental autoimmune encephalitis (EAE) mouse model in which the disease process is induced by administration of myelin peptides. Development of EAE requires infiltration of inflammatory cytokine-generating monocytes and macrophages, and auto-reactive T cells, into the CNS. Very late antigen-4 (VLA-4, α4β1) is an integrin molecule that plays a role in inflammatory responses by facilitating the migration of leukocytes across the blood-brain barrier during inflammatory disease, and antibodies against VLA-4 exhibit therapeutic efficacy in mouse and monkey MS models. Here we report that the tellurium compound AS101 (ammonium trichloro (dioxoethylene-o,o’) tellurate) ameliorates EAE by inhibiting monocyte ant T-cell infiltration into the CNS. CD49d is an alpha subunit of the VLA-4 (α4β1) integrin. During the peak stage of EAE, AS101 treatment effectively ameliorated the disease process by reducing the number of CD49d+ inflammatory monocyte/macrophage cells in the spinal cord. AS101 treatment markedly reduced the pro-inflammatory cytokine levels, while increasing anti-inflammatory cytokine levels. In contrast, AS101 treatment did not affect the peripheral populations of CD11b+ monocytes and macrophages. AS101 treatment reduced the infiltration of CD4+ and CD49+/VLA4 T cells. In addition, treatment of T cells from MS patients with AS101 resulted in apoptosis, while such treatment did not affect T cells from healthy donors. These results suggest that AS101 reduces accumulation of leukocytes in the CNS by inhibiting the activity of the VLA-4 integrin, and provide a rationale for the potential use of Tellurium IV compounds for the treatment of MS.

BackgroundRheumatoid arthritis (RA) is the most common autoimmune inflammatory arthritis in adults. In recent years, the availability of therapeutic options for RA management has significantly increased. Yet, not all patients receive the recommended therapy (1 and real-world data on RA treatment patterns are limited.ObjectivesWe aimed to identify and characterize RA patients, to examine their past and current treatment patterns, and identify factors associated with non-treatment.MethodsWe conducted a retrospective study using the computerized database of Maccabi Healthcare Services (MHS), a large health maintenance organization. Prevalent RA patients on Dec 31 2020 were defined by: ICD-9 code 714.X (≥2 diagnoses by a rheumatologist and/or ≥2 diagnoses by a primary care physician [PCP] and/or ≥1 diagnoses from a hospital with one diagnosis from a PCP); ≥1 rheumatoid factor (RF) test performed; age ≥18 years on the first diagnosis; first diagnosed before Dec 31 2018; MHS members for ≥12 months before and after the first RA diagnosis. RA patients also had to meet at least one of the following criteria: ≥1 purchase of disease modifying anti-rheumatic drugs (DMARDs) and/or ≥2 separate RA diagnoses by a rheumatologist and/or ≥1 positive RF test or anti-cyclic citrullinated peptide antibodies (anti-CCP) test. Patients were characterized according to socio-demographic and clinical factors. Treatment patterns with DMARDs were examined during 2000-2020. Multivariate logistic regression model was used to identify factors associated with current DMARDs treatment in 2020.ResultsWe identified 8301 eligible RA patients (Table 1). The proportion of patients initiating treatment with any DMARDs within 12 months of diagnosis gradually increased from 37.8% in 2000 to 69.3% in 2010 and reached 80.0% for those first diagnosed in 2018. During 2000-2009, 60.0%-63.4% of the RA patients were not treated and during 2010-2020 53.8%-57.9% were not treated. Following the introduction of bDMARDs, the proportion of those using bDMARDs and/or tsDMARDs increased (Figure 1). The median time to treatment with the first bDMARDs decreased during follow-up, from 9 years (IQR 6.0-13.0) among those diagnosed in 2000 to 3 years (IQR 1.0-5.0) in those diagnosed in 2009, and to 1 year in those diagnosed in 2018 (IQR 0-1.0). In 2020, only 44.3% of the RA patients were treated with any DMARD. Patients with disease duration of 5-<10 years and disease duration of ≥10 years, were less likely to be treated with any DMARD in 2020 compared to those with disease duration of <5 years (OR 0.7, 95% CI 0.6-0.8; OR 0.6, 95% CI 0.5-0.7, respectively). Seropositive patients and those who initiated treatment with any DMARD within the first 12 months of diagnosis were more likely to be treated (OR 1.8, 95% CI 1.7-2.0; OR 3.5, 95% CI 3.2-3.9, respectively).ConclusionWe observed an increase in the proportion of RA patients initiating treatment with any DMARD in the first year after diagnosis over the last two decades. Yet, about 55% of all RA patients were untreated in 2020, especially those with longer disease duration. Efforts should be made to optimize the disease management.References[1]Kern D. Rheumatol Ther (2018) 5:355–369.[2]Steffen A. Rheumatology International (2018) 38:2111–2120.Table 1.Baseline characteristics of RA patients (n=8301)Age, Dec 31 2020 (SD)63.6 (14.0)Sex, Female6,183 (74.5%)Socio-economic statusLow1,487 (17.9%)Medium4,430 (53.4%)High2,384 (28.7%)Age at diagnosis (SD)50.9 (14.1)Disease duration in years, Dec 31 2020 (SD)12.2 (6.2)Disease duration<5 years1207 (14.5%)5-<10 years1901 (22.9%)≥10 years5193 (62.6%)Seropositive, ever (rheumatoid factor and/or anti-CCP test)4,429 (53.4%)Oral corticosteroids use, 2020222 (2.7%)ComorbiditiesIschemic heart disease719 (8.7%)Dyslipidemia975 (11.7%)Hypertension4035 (48.6%)Diabetes1,806 (21.8%)Osteoporosis2,973 (35.8%)Malignancy1,582 (19.1%)1Mean (SD); n (%)Figure 1.Treatment pattern among prevalent RA patients 2000-2020Acknowledgements:NIL.Disclosure of InterestsVered Rosenberg Grant/research support from: Gilead Sciences Israel, Ori Elkayam: None declared, Gabriel Chodick Grant/research support from: Gilead Sciences Israel, Meital Halperin-Sheinfeld Employee of: Gilead Sciences Israel, Victoria Furer: None declared.